Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Luis M Montaño
 -- 4478 2023-05-12 21:06:50 |
2 format correct
Catherine Yang
 + 1 word(s) 4479 2023-05-15 04:34:33 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Romero-Martínez, B.S.; Sommer, B.; Solís-Chagoyán, H.; Calixto, E.; Aquino-Gálvez, A.; Jaimez, R.; Gomez-Verjan, J.C.; González-Avila, G.; Flores-Soto, E.; Montaño, L.M. Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens. Encyclopedia. Available online: https://encyclopedia.pub/entry/44222 (accessed on 03 May 2024).
Romero-Martínez BS, Sommer B, Solís-Chagoyán H, Calixto E, Aquino-Gálvez A, Jaimez R, et al. Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens. Encyclopedia. Available at: https://encyclopedia.pub/entry/44222. Accessed May 03, 2024.
Romero-Martínez, Bianca S., Bettina Sommer, Héctor Solís-Chagoyán, Eduardo Calixto, Arnoldo Aquino-Gálvez, Ruth Jaimez, Juan C. Gomez-Verjan, Georgina González-Avila, Edgar Flores-Soto, Luis M. Montaño. "Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens" Encyclopedia, https://encyclopedia.pub/entry/44222 (accessed May 03, 2024).
Romero-Martínez, B.S., Sommer, B., Solís-Chagoyán, H., Calixto, E., Aquino-Gálvez, A., Jaimez, R., Gomez-Verjan, J.C., González-Avila, G., Flores-Soto, E., & Montaño, L.M. (2023, May 12). Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens. In Encyclopedia. https://encyclopedia.pub/entry/44222
Romero-Martínez, Bianca S., et al. "Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens." Encyclopedia. Web. 12 May, 2023.
Airway Smooth Muscle Calcium Handling Mechanisms and Estrogens
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24097879

Cell calcium (Ca2+) homeostasis is maintained by a finely tuned Ca2+ signaling system made-up of numerous Ca2+ transporters (channels, exchangers, and pumps) regulating the influx and efflux of this cation from the cytoplasm to preserve its balance. Ca2+ homeostasis is essential for the cell. As a second messenger, Ca2+ signaling regulates various cellular processes that depend on the Ca2+ concentration. It is well known that Ca2+ regulates exocytosis, contraction, protein phosphorylation, dephosphorylation, metabolism, gene transcription, fecundation, cell proliferation, and even apoptosis. In the ASM, Ca2+ homeostasis keeps intracellular basal Ca2+ concentrations (b[Ca2+]i) at around 100–150 nM, while Ca2+ concentrations in the intracellular stores and extracellular space are higher (5–10 mM and 2 mM, respectively) creating a large chemical gradient in favor of Ca2+ influx into the cytosol. In order to regulate [Ca2+]i, numerous proteins exist to facilitate the cellular influx and efflux of Ca2+. Among the calcium-handling proteins, the voltage-dependent Ca2+ channels (VDCCs), store-operated Ca2+ channels (SOCCs), receptor-operated Ca2+ channel (ROCCs), transient receptor potential channels (TRPs), and the Na+/Ca2+ exchanger in its reverse form (NCXREV) as influx mechanisms located in the cellular membrane can be included. On the other hand, the Na+/Ca2+ Exchanger (NCX) and the plasma membrane Ca2+ ATPase (PMCA) are efflux mechanisms located in the cellular membrane.

estrogen airway smooth muscle channels exchangers

1. Voltage-Dependent Ca2+ Channels

Extracellular Ca2+ entry is primordial in Ca2+ signaling, and its influx is primarily driven by an electrochemical gradient. In ASM, both L- type VDCCs (Long Lasting Currents voltage-dependent Ca2+ channels) and T-type VDCCs (Transient Currents voltage-dependent Ca2+ channels) are expressed, but L-VDCC is the predominant type in human ASM and various other species [1][2][3][4][5][6][7][8][9][10]. In this sense, the preincubation with E2 at physiological levels can inhibit L-VDCCs non-genomically (Figure 1) in a concentration-dependent manner in human ASM (hASM) stimulated with histamine, with a more pronounced effect when using an ERα-selective agonist, which was not observed when using an ERβ selective agonist (Table 1) [11]. This could be partially due to the localization of the receptors since ERβ is minimally present in the plasma membrane, where non-genomic effects could take place [11]. This effect seems to have a biphasic response since at supraphysiological levels, E2 also inhibits L-VDCCs non-genomically in guinea pig ASM, as demonstrated through electrophysiological studies (Table 1) [12]. Both estrogen receptors seem to have different signaling pathways. They serve distinct purposes, both in physiological and pathological conditions. For instance, in human ASM cells from an asthmatic, an increase in the expression of the different variants of both receptors at different degrees has been reported, although their role in asthma pathophysiology remains to be elucidated [13]. Furthermore, chronic exposure (24 h, genomic effect) to estrogens in hASM cells from asthmatics and non-asthmatics seems to have opposing effects on [Ca2+]i. This phenomenon seems to depend on the type of receptor activated. An ERα-specific agonist ((R,R)-THC) augmented the [Ca2+]i response induced by histamine in both asthmatic and non-asthmatic hASM cells. Meanwhile, an ERβ-specific agonist (DPN), decreased the [Ca2+]i response induced by histamine in asthmatic and non-asthmatic hASM cells. The effect observed on the [Ca2+]i response with activation of ERβ signaling appears to implicate the inhibition of L-VDCC (Figure 1) (Table 1) [14]. Interestingly, E2, (as a non-selective ER agonist) at physiological concentrations did not show significant changes in the [Ca2+]i response to different agonists in ASM [14]. Unfortunately, the genomic effects of estrogen on L-VDCC expression, have not been explored in ASM cells yet. In comparison, ovariectomy (OVX) induced an increase in the channels’ expression in rat aorta. Interestingly, treatment with E2 downregulated the channels’ mRNA expression, and treatment with E2 and tamoxifen (an ER blocker) had a similar effect as E2 alone [15].
Figure 1. Calcium handling mechanisms in airway smooth muscle and their modulation by estrogens. E2 through non-genomic effects inhibits SOCCs, and the chronic exposure to an ERβ-specific agonist decreases the expression of STIM1 and Orai1, and an ERα-specific agonist increases the expression of STIM1 and Orai1.The genomic effect of E2 increases the expression of CD38, although the non-genomic effect is still unknown. E2 acutely inhibits the LVDCC and the chronic exposure, via ERβ pathway, inhibits this channel. In the sarcoplasmic reticulum, the chronic exposure with an ERβ-specific agonist inhibits the increase in SERCA expression caused by exposure to TNF-α and IL-13. The genomic and non-genomic effects of E2 over RyR2, IP3R1, NCX and PMCA are still not reported. EC, extracellular; Ac, Acute; Ch, Chronic; IP3, inositol 1,4,5-trisphosphate; [Ca2+]i, intracellular calcium concentration; [Ca2+]e, extracellular calcium concentration; [Ca2+]SR, sarcoplasmic reticulum calcium concentration; E2, 17β estradiol; ERα, estrogen receptor α; ERβ, estrogen receptor β; L-VDCC, L-type voltage dependent Ca2+ channel; SOCC, store-operated Ca2+ channel, NCX, Na+/Ca2+ Exchanger; PMCA, plasma membrane Ca2+ ATPase; IP3R, inositol 1,4,5-trisphosphate receptor; RyR, Ryanodine receptor; SERCA, sarcoplasmic reticulum Ca2+ ATPase; FKBP-12.6, 12.6 kDa FK506-binding protein; Orai1; STIM1, stromal interacting molecule; SARAF, Store-operated Ca2+ entry-associated regulatory factor.
Table 1. Summary of the effects of estrogens on the calcium handling mechanisms in the airway smooth muscle.
  Acute Chronic
Calcium Handling Mechanisms Pathway Effect Pathway Effect
Voltage-dependent Ca2+ channels (VDCCs) ERα Inhibition [11][12] ERβ Inhibition [14]
Store-Operated Calcium Channels (SOCCs) ERα Inhibition via STIM1 phosphorylation [11][16] ERβ Downregulated STIM1 and Orai1 expression [17]
ERα Upregulated STIM1 and Orai1 expression [17]
Ryanodine Receptor (RyR) Unknown Unknown ERs Upregulates CD38 expression [18]
IP3 Receptor (IP3R) Unknown Unknown Unknown Unknown
Na+/Ca2+ Exchanger (NCX) No effect No effect [11] Unknown Unknown
Plasma Membrane Ca2+ ATPase (PMCA) Unknown Unknown Unknown Unknown
Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) No effect No effect ERβ Upregulates SERCA2 expression [14]

2. Store-Operated Calcium Channels

Another group of calcium channels that regulates Ca2+ influx to the cytosol is SOCCs, considered non-selective cation channels. Its activity depends on the SR Ca2+depletion and its goal is to contribute to the refilling of internal Ca2+ stores [19]. To carry out their function following SR depletion, these channels must assemble into a complex formed by two proteins: Orai1 (calcium release-activated calcium channel protein 1) and STIM1 (stromal interacting molecule) [19]. When at rest, STIM1 is bound to Ca2+. When Ca2+ levels begin to diminish in the SR, STIM1 disassociates from Ca2+, and this change causes STIM1 molecules to cluster and translocate to a region in proximity to the plasma membrane [19][20][21]. Orai1 is a transmembrane protein located in the plasma membrane. In basal conditions, this protein is a dimer, but when STIM1 clusters are formed, they interact with Orai1 and enable them to form tetramers, forming selective Ca2+ pores that allow Ca2+ influx [19][21]. This mechanism is negatively regulated by the SR transmembrane protein SARAF (store-operated Ca2+ entry-associated regulatory factor). When SARAF interacts with STIM1, it prevents spontaneous activation or the interaction between STIM1-Orai1 [19][22][23]. On the other hand, transient receptor potential canonical (TRPC) channels also play an important role in Ca2+ homeostasis, and it is known that the TRPC3 isoform prevails in ASM cells [1]. Recently, the STIM1-Orai1 complex was found to interact with TRPC channels required for their activation [24][25]. Other members of the TRP channel family are vanilloid (TRPV) receptors, ankyrin (TRPA) and melastatin (TRPM), of which TRPV1 and TRPV4 have been identified in ASM cells (Figure 1) [1][26][27][28][29].
Given the importance of SOCCs in Ca2+ homeostasis, the effects that E2 could have on their regulation is of increasing interest. Townsend et al. determined that the decrease in Ca2+ induced by the acute exposure to physiological concentrations of E2 observed in the Ca2+ response induced by histamine in hASM cells (Table 1) [11], was in part due to inhibition of SOCCs observed as a diminished SR refilling (Figure 1) [30]. On the other hand, the chronic effects of the estrogen receptor signaling on SOCCs modulation have also been explored in healthy and asthmatic hASM cells. The chronic exposure (24 h) to an ERβ-selective agonist (WAY-200070) downregulated the expression of STIM1 and Orai1 measured through Western blot (Figure 1), and consequently produced a decrease in [Ca2+]i. This effect was observed in hASM from non-asthmatics, but was more pronounced in asthmatics [17]. When exposed to an ERα-selective agonist (propyl pyrazole triol at 10 nM) for 24 h, an opposite effect was observed. SOCCs Ca2+ influx was increased, and the expression of STIM1 and Orai1 was also increased (Figure 1) (Table 1) [17].
Cigarette smoke (CS) is a common risk factor associated with many airway diseases, and asthmatic women exposed to CS tend to have a worse asthmatic response; therefore, the effects of CS and E2 on ASM Ca2+ regulation were explored [16]. As a result, it was defined that, in hASM cells, a 24 h exposure to CS extract induces a significant increase in the Ca2+ response to histamine. On the other hand, acute exposure to nanomolar E2 concentrations inhibits the Ca2+ response to histamine partially via inhibition of SOCCs [11]. When exposed to CS extract, this E2 effect was blunted [16]. Chronic exposure to CS extract (24h exposure to 1% or 2% CS) also seems to increase the expression of ERα and ERβ, leading to investigate if a differential ER regulation was present. As observed before, the acute effect on Ca2+ was present when using an ERα-specific agonist but not an ERβ-selective agonist [11]. This effect was absent when the cells were previously exposed to CS extract [16]. Therefore, CS extract enhances [Ca2+]i through the dysregulation of ER signaling, and blunts the acute reduction in [Ca2+]i and subsequent force generation resultant from ERα activation, more so in asthmatic patients than in healthy subjects. E2 also non-genomically inhibited STIM1 phosphorylation, while pre-exposure to CS extract for 24 h abolished this E2 effect [16].
Studies in other cellular types point out the physiological implications of E2-mediated regulation of SOCCs. In airway epithelial cells, E2 (10 nM) acute (15 min) exposure can reduce STIM1 phosphorylation, preventing the formation of STIM1 clusters from interacting with and activating Orai1, decreasing SOCCs activity. This decrease in SOCCs influx also affects Ca2+ activated Cl− channels colocalized with Orai1, impacting mucus hydration [31]. In mouse embryonic stem cells (mESCs), the treatment with physiological concentrations of E2 (1 pM and 1nM) during 24 h enhanced cellular proliferation in a concentration-dependent manner. The effect was through SOCCs activity and could be reverted by SOCCs blockers (2-APB 0.3 µM) [32]. As already mentioned, Ca2+ homeostasis disruption can lead to pathologies. Such is the case in various cancer types, where dysfunction of Ca2+ homeostasis has been implicated. Epithelial ovarian cancer (EOC) is closely tied to E2 regulation, and the effects that E2 could have over Orai1 and the different pathological processes in EOC have been explored [33]. After 12 h exposure with E2 (at a micromolar range), Orai1 expression increased in SK-OV-3 cells (an EOC cell line), with the most significant effect observed at 1 µM, leading to an increase in [Ca2+]i. E2, through Orai1, positively regulated cellular and migration (by CDK6 and MMP-1 pathways, respectively), and suppressed cellular proliferation apoptosis through caspase3 expression regulation [33]. In another study in EOC cells, the chronic exposure to E2 (10 nM–1 µM for 24, 48, and 72 h) increased the mRNA levels and protein expression of TRPC3, and via TRPC3 increased cellular proliferation and migration [34]. E2 upregulates TRPV1 expression, participating in pain induction, endometriosis and bone resorption. TRPV1 mRNA levels have been shown to be decreased by E2. Through GPR30, E2 modulates TRPV1 phosphorylation to participate in pain sensitization. Through non-genomic effects, E2 has been shown to both potentiate and decrease capsaicin-evoked currents of TRPV1 [35]. Yang et al., found that TRPV6 expression was increased in human endometrium after E2 treatment [36]. Similarly, in mouse uterine tissues, TRPV5 and TRPV6 were upregulated with E2 treatment; bisphenol A (BPA) that has estrogenic effects, also significantly increased TRPV5 and TRPV6 expression but not to the degree of E2 [37]. Upregulation of TRPA1 by E2 participates in the pathophysiology of endometriosis. Furthermore, through non-genomic effects, E2 increments TRPA1 activation in glucose-induced insulin secretion [35].
Through these studies, the researchers can observe the diverse interactions that estrogens can have over SOCCs modulation and the repercussions in different pathological states.

3. Ryanodine Receptor

In the SR, one of the mechanisms in charge of the Ca2+ efflux to the cytosol is the RyR. In mammals, three isoforms are found -1, -2, and -3; in mouse ASM, RyR1, and RyR2 are the predominant isoforms, with minimal expression of RyR3 [1][38][39]. It has been found that he endogenous modulation of RyR activity in ASM cells is through the CD38/Cyclic ADP-ribose signaling pathway, regulating [Ca2+]i. The membrane-bound protein CD38 synthesizes or degrades cADPR, which functions as a ligand for the protein FKBP-12.6 (12.6 kDa FK506-binding protein). In turn, FKBP112.6 binds to the RyR, providing stabilization and reducing the opening probability of the channel. When cADPR binds to the regulatory protein, this causes a conformational change in the RyR, activating Ca2+ release to the cytosol [40][41][42]. Alterations in this signaling pathway, such as the upregulation of CD38 induced by TNF-α, IL-1β, and IFN-γ, can lead to an asthmatic phenotype of the ASM cells, characterized by airway hyperresponsiveness (AHR) that might develop when an already enhanced [Ca2+]i concentration is increased further after Gq protein coupled receptor (GPCR) activation [40][42]. Until now, no non-genomic effects of estrogens over RyRs in ASM cells have been reported. However, in rat cardiomyocytes, bisphenol A (BPA) and bisphenol S (BPS) (estrogenic endocrine-disrupting chemicals) have shown acute effects over RyR activity [43][44]. At nanomolar concentrations, both substances significantly altered characteristic RyR-mediated SR Ca2+ sparks by transiently and rapidly (30s–5 min) increasing the phosphorylation of RyR at the serine 2808 site through protein kinase A(PKA) activity, as well as phospholamban (PLB, a protein that binds to SERCA and regulates its activity) by Ca2+/CaM-dependent protein kinase II (CAMKII). This effect was completely abolished when a selective-ERβ blocker was used (PHTPP), but not with a selective-ERα blocker (MPP), indicating that this effect is dependent on the ERβ signaling pathway [43][44].
In mouse ASM cells, long term exposure (24–48 h) to E2 (at physiological levels) was shown to upregulate the expression of CD38 (Figure 1) (Table 1) [18]. As mentioned before, CD38 is a key component in the mechanisms in charge of Ca2+ homeostasis by regulating the activity of RyRs. The genomic effect that estrogens could have directly on RyR expression in ASM cells has yet to be explored. In other models, estrogens have shown to impact RyR expression. In uterine arteries from pregnant sheep (a period of higher estrogenic levels), all three isoforms of RyR were upregulated, causing an increase in Ca2+ sparks. Additionally, in uterine arteries from nonpregnant sheep treated ex vivo with estrogen and progesterone mimicking pregnancy conditions, a similar upregulation of RyR was observed [45]. In female rat cardiomyocytes, RyR2 is expressed at higher levels than in male rats [46][47][48]. In contrast, other reports state that in female cardiomyocytes, RyR2 phosphorylation by CaMKII/PKA is reduced, causing lower Ca2+ sparks [46][49][50]. Another possible mechanism of modulation through the ER signaling pathway is by direct protein–protein interaction. Recently, it was discovered that ERβ has an atypical non-genomic effect over the RyR, in the neuronal cell line HT-22. In these cells, RyR2 and ERβ have varying levels of co-localization, and in electrophysiological studies using RyRs from mouse brain incorporated into artificial lipid bilayers, the application of unliganded (E2-free) ERβ1 monomers caused a significant increase in single-channel currents under basal [Ca2+]i of 100 nM. This effect caused by the addition of ERβ1 could indicate a synergic interaction with Ca2+ and RyR that increases the open probability of the channel and could potentiate RyR activity of Ca2+-induced Ca2+-release [51]. The modulatory activity that the complex E2-ERβ1, or the other isoforms of the ERβ and ERα, could have on the RyR remains to be determined. It might be possible that RyR-ERs interact in the ASM. This probability warrants further and more precise studies.

4. IP3 Receptor

The other mechanism that releases Ca2+ from the SR is the IP3R, activated by its agonist IP3 (inositol 1,4,5-trisphosphate) [1][19][38]. As extensively known, when an agonist binds to a membrane GPCRs, phospholipase Cβ (PLCβ) is activated and hydrolyzes the lipid phosphatidylinositol 4,5-biphosphate, generating IP3 and diacylglycerol (DAG) [1][19][38]. In mammals, three isoforms of the IP3R are expressed (IP3R1, -2, and -3); all isoforms have been identified in ASM (Figure 1) [1][52][53][54][55]. Afterward, IP3 binds to the IP3R in the SR, generating the release of Ca2+ from these internal stores. This pathway has usually been implicated in the agonist-induced contraction of the ASM. However, IP3R participation in the bronchodilation mechanism induced by the TAS2R pathway (Type 2 taste receptor) has also been proposed [56][57].
The genomic and non-genomic effects that estrogens could have on the IP3 signaling pathway in ASM cells remain to be explored, but estrogen modulation in other cell types has been reported (Figure 1). E2 (1 nM) increased IP3 production after 6 h of exposure (non-genomic effect) in rat oviduct smooth muscle cells, a phenomenon mediated through an increase in PLC activity [58]. In HEPG2 cells (human hepatoma cell line), the addition of E2 (nanomolar range) induced a rapid increase in IP3 production [59], which was also observed in female rat chondrocytes [60]. Treatment of rat osteoblasts with E2 (100 pM) caused rapid transient increases in [Ca2+]i via the PLCβ-IP3 pathway [61]. E2 treatment has been shown to cause rapid increases in [Ca2+]i through an ER interaction with type 1a metabotropic glutamate receptors (mGluR1a), activating the PLCβ-IP3 pathway in female rat astrocytes [62]. Among the genomic effects, it has been reported that IP3R1 expression is suppressed after 48h exposure to E2 (10 nM) in human g-292 osteosarcoma cells and rat osteoblasts [63]. In rat choroidal plexus epithelial cells, E2 (nanomolar range) downregulated the expression of receptors TAS2R109 and -144, as well as PLCβ2, resulting in a decrease in [Ca2+]i in response to TAS2R agonists [57][64].

5. Na+/Ca2+ Exchanger

During the membrane depolarization phase in ASM, an accumulation of Na+ underneath the plasma membrane takes place, influencing the Ca2+ homeostasis through the generation of local concentration gradients. The consequent modulation of the [Ca2+]i through the Na+ gradients results in various physiological processes, depending on the magnitude, time and region, including contraction, proliferation, protein synthesis and apoptosis, among others [65].
The NCX serves as one of the [Ca2+]i buffer mechanisms by extruding Ca2+ from the cytosol to the extracellular space [1][38]. The NCX carries three Na+ ions into the cytosol while extruding one Ca2+; three isoforms, NCX1, -2, and -3 are known, and the most prominent isoform in ASM is the variant NCX1.3 [1][66][67][68][69]. The participation of NCX in Ca2+ homeostasis in ASM seems to be minor (Figure 1) [1][70], and apparently its reverse mode (NCXrev) has higher importance in ASM physiology. Interestingly, NCXrev introduces Ca2+ and extrudes Na+ [1]. NCXrev plays a preponderant role in agonist-stimulated ASM, as for instance, an inhibitor of NCXrev (KB-R7943, 10 µM) attenuated the [Ca2+]i increase and contraction induced by carbachol (CCh 100 µM) [71]. The Ca2+ influx caused by the removal of Na+ in hASM and mouse ASM was blocked by KB-R7943 [71].
Seemingly, NCXrev also has an important function during oscillatory contractions in mouse ASM induced by potassium channel blockade with tetraethylammonium chloride (TEA). In this experiment, two pattern changes of [Ca2+]i were induced. One was a high-frequency oscillation, and the other a low-frequency rhythmic oscillation. Both types of Ca2+ changes participate in triggering ASM contraction, and they might participate in other physiological processes in the ASM. Remarkably, these oscillations augment [Ca2+]i, an increase that activates NCX, initiating the relaxation phase by extruding Ca2+ [72]. Alterations of the NCX also participate in pathological conditions; TNF-α or IL-13 treatment of hASM cells upregulated the expression of NCX1, and the treatment with KB-R7943 abolished methacholine induced AHR in an allergic mouse model [71][73]. This was also observed in a chronic allergen-induced AHR murine model, where NCX1 was upregulated and had higher NCXrev activity [74].
The effects of E2 on NCX modulation have not been as extensively investigated as other mechanisms. The acute exposure to E2 in hASM cells did not have a significant effect on NCX (Table 1) [11], and the effects of a chronic exposure to E2 on NCX in ASM cells has not been explored yet (Figure 1). Likewise, the participation of NCX in other tissues’ physiology is inconclusive. The chronic treatment with E2 (3 days) in prepubescent female rats resulted in downregulation of NCX1 expression in the esophagus [75]. In female rat cardiomyocytes, OVX (ovariectomy) caused downregulation of NCX expression that was reversed by E2 treatment [46][76]. Similarly, in female rabbit cardiomyocytes, NCX expression was greater than in males [46][77][78], and cardiomyocytes incubated with E2 1 nM during 24 h presented a 50% increase in NCX1 protein expression and INCX density mediated by ERs [78]. Contrary to these findings, OVX or E2 replacement therapy did not alter NCX expression in rat cardiomyocytes. However, NCX activity was significantly increased after OVX in a protein kinase A (PKA)-dependent way; this effect was reverted after E2 treatment [46][79]. Likewise, in cardiomyocytes from OVX guinea pigs, NCX activity was increased by 20%, and this effect was reverted with E2 treatment [46][80]. Moreover, E2 supplementation has been found to have a cardioprotective effect in ischemia/reperfusion injury models [81].
In this sense, NCX overexpression models after myocardial infarction (MI) caused an overload in [Ca2+]i in male mice but not in female mice. Male mice cardiomyocytes, when exposed to E2 (nanomolar range), decreased [Ca2+]i post-MI in a concentration-dependent manner [81]. Interestingly, in a group of female transgenic mice, the NCX overexpression did not lead to [Ca2+]i overload, indicating the protective role of E2 to compensate for the greater activity of NCX [81]. These findings point out that E2 exerts a protective function in cardiac myocytes. Indeed, further research clarified that post-MI E2-confered protection was mediated by NCX. In another study, it was confirmed that the myocardial contractile function (left ventricular developed pressure, dP/dtmax, dP/dtmin) in male transgenic NCX overexpression mice was significantly higher than in their WT counterparts, as well as in OVX transgenic females, but not in the transgenic or SHAM transgenic female groups. These results implicate NCX in both the contractile and relaxation aspects of the heartbeat. In the post-MI/reperfusion injury phase, the function recovery in transgenic males was lower than in WT males; however, female WT and transgenic NCX mice had a similar recovery, compared with the significantly diminished recovery in the OVX group. This post-ischemic functional recovery pattern coincides with the lower recovery of energy metabolites (ATP and phosphocreatine) as well as the alternans (heartbeats of alternating large and small amplitude at equal intervals) observed only in the hearts of the male transgenic and female OVX transgenic mice, corresponding to [Ca2+]i overload. These findings suggest a protective role of estrogen over the NCX activity during ischemic/reperfusion injury [82].
Furthermore, E2′s protective capacities were also observed in neurons, where nanomolar concentrations of E2 exerted rapid effects over the NCX function, increasing the outward Ca2+ current and decreasing the Ca2+ influx mediated by NCX; this effect was potentiated by insulin-like growth factor 1 (IGF-1) [83]. These effects seem to be independent of the canonical estrogen signaling pathways, since the presence of an inhibitor of estrogen receptors (ICI182780, 10 µM) did not alter the results. The non-genomic activity of E2 over NCX in neurons leads to maintaining [Ca2+]i at lower levels, preventing the activation of Ca2+-dependent apoptosis. These mechanisms could be especially useful to counteract the cytotoxicity induced by glutamate through NMDA or AMPA receptor activation [83][84].

6. Plasma Membrane Ca2+ ATPase

To restore [Ca2+]i to basal levels after increases induced by agonist stimulation, Ca2+ can be pumped across the membrane and out of the cell against its electrochemical gradient, expending ATP during the process [1][19][38][85]. This mechanism is achieved by the ASM plasma membrane ATPase (PMCA) that has four different isoforms: PMCA1, -2, -3 and -4, but only PMCA1 and PMCA4 are expressed in this tissue (Figure 1) [1][85]. PMCA activity in ASM cells has been implicated in many intracellular processes, including contraction regulation [1], cellular proliferation [85], and even apoptosis [85]. It is possible that dysfunction of this protein could lead to an increase in [Ca2+]i and favor AHR [1][85].
Modulation of PMCA in ASM cells by estrogen, either through genomic or non-genomic actions, has not been described (Figure 1). However, this phenomenon has been studied in other cellular types. For instance, in prepubescent female rats treated for 3 days with E2 (40 µg/kg/day), the PMCA1 expression in the esophagus was decreased [75]. In MCF-7 cells (breast cancer cell line), PMCA4b isoform expression was increased by E2 (1 nM) treatment in a way mediated by ERα [86]. Conversely, E2 treatment for 24 h decreased the expression of the isoforms PMCA2 and -4 in human fibroblast-like synovial cells (HFLS) and in mouse macrophage-like cells in a dose-dependent manner [87]. In another study, E2 exposure for 24 h did not alter PMCA expression in distal tubule kidney cells; however, PMCA activity was significantly enhanced [88]. In human endometrium, PMCA1 expression was significantly upregulated when treated with E2 (physiological range) for 48 h [36], compared to the decrease of PMCA1 expression in mouse uterus following E2 treatment [37]. E2 has also been described to participate in mechanical pain sensitivity through PMCA2. In female mice, OVX increased mechanical pain sensitivity through PMCA2; this was reversed with E2 supplementation, in a ER-mediated way [89]. It should be noted that alterations in the Ca2+ machinery might participate in various pathophysiological processes in accordance with the type of cell implicated.

7. Sarcoplasmic Reticulum Ca2+ ATPase

Another essential Ca2+-pump that participates in intracellular Ca2+ reuptake that is located on the SR membrane of ASM cells is SERCA. It is in charge of driving Ca2+ ions against its electrochemical gradient by ATP consumption to reestablish b[Ca2+]i and restoring depleted Ca2+ internal stores [1][19][85]. Three isoforms of the SERCA protein are known: SERCA1, -2, and -3, with various alternative splicing isoforms. ASM expresses isoforms SERCA2a and 2b, which predominate [1][90][91]. Alterations in SERCA expression or activity can lead to increases in [Ca2+]i, a phenomenon that has been linked to an asthmatic ASM phenotype that contributes to airway remodeling and hyperresponsiveness [1][85][91][92][93].
Interestingly, hASM cells exposed to E2 apparently showed no acute effects on SERCA activity (Figure 1) [11]. Contrastingly, the estrogen-induced genomic effects on SERCA were explored in hASM cells. They were treated with E2 (1 nM), ERα agonist (PPT, 10 nM) or an ERβ agonist (WAY, 10 nM) for 2 hrs, and then incubated with TNF-α or IL-13. The Ca2+ response to histamine in the presence of TNF-α or IL-13 was significantly higher compared to the vehicle. A similar response was observed in the E2 and PPT groups, but the effect was reverted in the WAY group, that showed a response similar to the vehicle group. The time of [Ca2+]i decay in the response induced by histamine was higher in the group treated with TNF-α or IL-13. This response was reversed by a treatment with WAY but not by E2 or PPT (Figure 1) [14]. These results were attributed to the treatment’s effects on SERCA2 expression, since there was a significant reduction in protein expression in the TNF-α or IL-13 treated cells, which was reverted in WAY treated cells but not in to those administered E2 or PPT (Table 1) [14].
The evidence indicates that [Ca2+]i can be modulated by estrogens by the coordinated participation of several target proteins, and that changes in Ca2+ availability induced by estrogens is dynamic and additive exerted through genomic and non-genomic events.

References

  1. Reyes-García, J.; Flores-Soto, E.; Carbajal-García, A.; Sommer, B.; Montaño, L. Maintenance of intracellular Ca2+ basal concentration in airway smooth muscle (Review). Int. J. Mol. Med. 2018, 42, 2998–3008.
  2. Janssen, L.J. T-type and L-type Ca2+ currents in canine bronchial smooth muscle: Characterization and physiological roles. Am. J. Physiol. 1997, 272, C1757–C1765.
  3. Montaño, L.M.; Barajas-Lopez, C.; Daniel, E.E. Canine bronchial sustained contraction in Ca2+-free medium: Role of intracellular Ca2+. Can. J. Physiol. Pharmacol. 1996, 74, 1236–1248.
  4. Sommer, B.; Flores-Soto, E.; Reyes-García, J.; Díaz-Hernández, V.; Carbajal, V.; Montaño, L.M. Na+ permeates through L-type Ca2+ channel in bovine airway smooth muscle. Eur. J. Pharmacol. 2016, 782, 77–88.
  5. Bean, B.P. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol. 1989, 51, 367–384.
  6. Yu, J.; Bose, R. Calcium channels in smooth muscle. Gastroenterology 1991, 100, 1448–1460.
  7. Green, K.A.; Small, R.C.; Foster, R.W. The properties of voltage-operated Ca2+-channels in bovine isolated trachealis cells. Pulm. Pharmacol. 1993, 6, 49–62.
  8. Hisada, T.; Kurachi, Y.; Sugimoto, T. Properties of membrane currents in isolated smooth muscle cells from guinea-pig trachea. Pflug. Arch. Eur. J. Physiol. 1990, 416, 151–161.
  9. Kotlikoff, M.I. Calcium currents in isolated canine airway smooth muscle cells. Am. J. Physiol. 1988, 254, C793–C801.
  10. Marthan, R.; Martin, C.; Amédée, T.; Mironneau, J. Calcium channel currents in isolated smooth muscle cells from human bronchus. J. Appl. Physiol. 1989, 66, 1706–1714.
  11. Townsend, E.A.; Thompson, M.A.; Pabelick, C.M.; Prakash, Y.S. Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2010, 298, L521–L530.
  12. Flores-Soto, E.; Reyes-García, J.; Carbajal-García, A.; Campuzano-González, E.; Perusquía, M.; Sommer, B.; Montaño, L.M. Sex steroids effects on guinea pig airway smooth muscle tone and intracellular Ca2+ basal levels. Mol. Cell. Endocrinol. 2017, 439, 444–456.
  13. Aravamudan, B.; Goorhouse, K.J.; Unnikrishnan, G.; Thompson, M.A.; Pabelick, C.M.; Hawse, J.R.; Prakash, Y.S.; Sathish, V. Differential Expression of Estrogen Receptor Variants in Response to Inflammation Signals in Human Airway Smooth Muscle. J. Cell. Physiol. 2017, 232, 1754–1760.
  14. Bhallamudi, S.; Connell, J.; Pabelick, C.M.; Prakash, Y.S.; Sathish, V. Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2020, 318, L112–L124.
  15. Tsang, S.Y.; Yao, X.; Wong, C.M.; Chan, F.L.; Chen, Z.Y.; Huang, Y. Differential regulation of K+ and Ca2+ channel gene expression by chronic treatment with estrogen and tamoxifen in rat aorta. Eur. J. Pharmacol. 2004, 483, 155–162.
  16. Sathish, V.; Freeman, M.R.; Long, E.; Thompson, M.A.; Pabelick, C.M.; Prakash, Y.S. Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle. Cell. Physiol. Biochem. 2015, 36, 1101–1115.
  17. Kalidhindi, R.; Ambhore, N.; Thompson, M.; Pabelick, C.; Prakash, Y.; Venkatachalem, S. Differential estrogen receptor signaling regulates store operated calcium entry in human airway smooth muscle. Am. J. Respir. Crit. Care Med. 2018, 197, A7259.
  18. Liu, Y.; Guo, Y.; Huang, W.; Deng, K.Y.; Qian, Y.; Xin, H.B. 17β-Estradiol Promotes Apoptosis in Airway Smooth Muscle Cells Through CD38/SIRT1/p53 Pathway. Front. Endocrinol. 2018, 9, 770.
  19. Krebs, J.; Agellon, L.B.; Michalak, M. Ca2+ homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling. Biochem. Biophys. Res. Commun. 2015, 460, 114–121.
  20. Peel, S.E.; Liu, B.; Hall, I.P. A key role for STIM1 in store operated calcium channel activation in airway smooth muscle. Respir. Res. 2006, 7, 119.
  21. Peel, S.E.; Liu, B.; Hall, I.P. ORAI and Store-Operated Calcium Influx in Human Airway Smooth Muscle Cells. Am. J. Respir. Cell Mol. Biol. 2008, 38, 744–749.
  22. Palty, R.; Raveh, A.; Kaminsky, I.; Meller, R.; Reuveny, E. SARAF Inactivates the Store Operated Calcium Entry Machinery to Prevent Excess Calcium Refilling. Cell 2012, 149, 425–438.
  23. Albarran, L.; Regodón, S.; Salido, G.M.; Lopez, J.J.; Rosado, J.A. Role of STIM1 in the surface expression of SARAF. Channels 2017, 11, 84–88.
  24. Liao, Y.; Erxleben, C.; Yildirim, E.; Abramowitz, J.; Armstrong, D.L.; Birnbaumer, L. Orai proteins interact with TRPC channels and confer responsiveness to store depletion. Proc. Natl. Acad. Sci. USA 2007, 104, 4682–4687.
  25. Xiao, J.-H.; Zheng, Y.-M.; Liao, B.; Wang, Y.-X. Functional Role of Canonical Transient Receptor Potential 1 and Canonical Transient Receptor Potential 3 in Normal and Asthmatic Airway Smooth Muscle Cells. Am. J. Respir. Cell Mol. Biol. 2010, 43, 17–25.
  26. Yocum, G.T.; Chen, J.; Choi, C.H.; Townsend, E.A.; Zhang, Y.; Xu, D.; Fu, X.W.; Sanderson, M.J.; Emala, C.W. Role of transient receptor potential vanilloid 1 in the modulation of airway smooth muscle tone and calcium handling. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2017, 312, L812–L821.
  27. Zhao, L.; Zhang, X.; Kuang, H.; Wu, J.; Guo, Y.; Ma, L. Effect of TRPV1 channel on the proliferation and apoptosis in asthmatic rat airway smooth muscle cells. Exp. Lung Res. 2013, 39, 283–294.
  28. Jia, Y.; Wang, X.; Varty, L.; Rizzo, C.; Yang, R.; Correll, C.; Phelps, P.; Egan, R.; Hey, J. Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2004, 287, L272–L278.
  29. Uchida, Y.; Izumizaki, M. Effect of menstrual cycle and female hormones on TRP and TREK channels in modifying thermosensitivity and physiological functions in women. J. Therm. Biol. 2021, 100, 103029.
  30. Flores-Soto, E.; Reyes-García, J.; Sommer, B.; Montaño, L.M. Sarcoplasmic reticulum Ca2+ refilling is determined by L-type Ca2+ and store operated Ca2+ channels in guinea pig airway smooth muscle. Eur. J. Pharmacol. 2013, 721, 21–28.
  31. Sheridan, J.T.; Gilmore, R.C.; Watson, M.J.; Archer, C.B.; Tarran, R. 17β-Estradiol Inhibits Phosphorylation of Stromal Interaction Molecule 1 (STIM1) Protein. J. Biol. Chem. 2013, 288, 33509–33518.
  32. Wong, C.K.; So, W.Y.; Law, S.K.; Leung, F.P.; Yau, K.L.; Yao, X.; Huang, Y.; Li, X.; Tsang, S.Y. Estrogen controls embryonic stem cell proliferation via store-operated calcium entry and the nuclear factor of activated T-cells (NFAT). J. Cell. Physiol. 2012, 227, 2519–2530.
  33. Lv, X.; Miao, C.; Liu, M.; Wang, X.; Wang, L.; Wang, D.J. 17β-Estradiol via Orai1 activates calcium mobilization to induce cell proliferation in epithelial ovarian cancer. J. Biochem. Mol. Toxicol. 2020, 34, e22603.
  34. Li, S.; Jiang, K.; Li, J.; Hao, X.; Chu, W.; Luo, C.; Zhu, Y.; Xie, R.; Chen, B. Estrogen enhances the proliferation and migration of ovarian cancer cells by activating transient receptor potential channel C3. J. Ovarian Res. 2020, 13, 20.
  35. Méndez-Reséndiz, K.A.; Enciso-Pablo, Ó.; González-Ramírez, R.; Juárez-Contreras, R.; Rosenbaum, T.; Morales-Lázaro, S.L. Steroids and TRP Channels: A Close Relationship. Int. J. Mol. Sci. 2020, 21, 3819.
  36. Yang, H.; Choi, K.C.; Hyun, S.H.; Jeung, E.B. Coexpression and estrogen-mediated regulation of TRPV6 and PMCA1 in the human endometrium during the menstrual cycle. Mol. Reprod. Dev. 2011, 78, 274–282.
  37. Tran, D.N.; Jung, E.-M.; Ahn, C.; Lee, J.-H.; Yoo, Y.-M.; Jeung, E.-B. Effects of Bisphenol A and 4-tert-Octylphenol on Embryo Implantation Failure in Mouse. Int. J. Environ. Res. Public Health 2018, 15, 1614.
  38. Berridge, M.J.; Bootman, M.D.; Roderick, H.L. Calcium signalling: Dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 2003, 4, 517–529.
  39. Lifshitz, L.M.; Carmichael, J.D.; Lai, F.A.; Sorrentino, V.; Bellvé, K.; Fogarty, K.E.; Zhuge, R. Spatial organization of RYRs and BK channels underlying the activation of STOCs by Ca2+ sparks in airway myocytes. J. Gen. Physiol. 2011, 138, 195–209.
  40. Jude, J.A.; Dileepan, M.; Panettieri, R.A.; Walseth, T.F.; Kannan, M.S. Altered CD38/Cyclic ADP-Ribose Signaling Contributes to the Asthmatic Phenotype. J. Allergy 2012, 2012, 289468.
  41. Fritz, N.; Macrez, N.; Mironneau, J.; Jeyakumar, L.H.; Fleischer, S.; Morel, J.-L. Ryanodine receptor subtype 2 encodes Ca2+ oscillations activated by acetylcholine via the M2 muscarinic receptor/cADP-ribose signalling pathway in duodenum myocytes. J. Cell Sci. 2005, 118, 2261–2270.
  42. Deshpande, D.A.; Walseth, T.F.; Panettieri, R.A.; Kannan, M.S. CD38-cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyperresponsiveness. FASEB J. 2003, 17, 452–454.
  43. Gao, X.; Liang, Q.; Chen, Y.; Wang, H.-S. Molecular Mechanisms Underlying the Rapid Arrhythmogenic Action of Bisphenol A in Female Rat Hearts. Endocrinology 2013, 154, 4607–4617.
  44. Gao, X.; Ma, J.; Chen, Y.; Wang, H. Rapid responses and mechanism of action for low-dose bisphenol S on ex vivo rat hearts and isolated myocytes: Evidence of female-specific proarrhythmic effects. Environ. Health Perspect. 2015, 123, 571–578.
  45. Hu, X.-Q.; Song, R.; Romero, M.; Dasgupta, C.; Huang, X.; Holguin, M.A.; Williams, V.; Xiao, D.; Wilson, S.M.; Zhang, L. Pregnancy Increases Ca2+ Sparks/Spontaneous Transient Outward Currents and Reduces Uterine Arterial Myogenic Tone. Hypertension 2019, 73, 691–702.
  46. Jiao, L.; Machuki, J.; Wu, Q.; Shi, M.; Fu, L.; Adekunle, A.; Tao, X.; Xu, C.; Hu, X.; Yin, Z.; et al. Estrogen and calcium handling proteins: New discoveries and mechanisms in cardiovascular diseases. Am. J. Physiol.-Heart Circ. Physiol. 2020, 318, H820–H829.
  47. Tappia, P.S.; Dent, M.R.; Aroutiounova, N.; Babick, A.P.; Weiler, H. Gender differences in the modulation of cardiac gene expression by dietary conjugated linoleic acid isomers. Can. J. Physiol. Pharmacol. 2007, 3–4, 465–475.
  48. Yaras, N.; Tuncay, E.; Purali, N.; Sahinoglu, B.; Vassort, G.; Turan, B. Sex-related effects on diabetes-induced alterations in calcium release in the rat heart. Am. J. Physiol.-Heart Circ. Physiol. 2007, 293, H3584–H3592.
  49. Bell, J.R.; Raaijmakers, A.J.; Curl, C.L.; Reichelt, M.E.; Harding, T.W.; Bei, A.; Ng, D.C.; Erickson, J.R.; Vila Petroff, M.; Harrap, S.B.; et al. Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart. Int. J. Cardiol. 2015, 181, 288–296.
  50. Farrell, S.R.; Ross, J.L.; Howlett, S.E. Sex differences in mechanisms of cardiac excitation-contraction coupling in rat ventricular myocytes. Am. J. Physiol.-Heart Circ. Physiol. 2010, 299, H36–H45.
  51. Rybalchenko, V.; Grillo, M.A.; Gastinger, M.J.; Rybalchenko, N.; Payne, A.J.; Koulen, P. The unliganded long isoform of estrogen receptor beta stimulates brain ryanodine receptor single channel activity alongside with cytosolic Ca2+. J. Recept. Signal Transduct. Res. 2009, 29, 326–341.
  52. Narayanan, D.; Adebiyi, A.; Jaggar, J.H. Inositol trisphosphate receptors in smooth muscle cells. Am. J. Physiol.-Heart Circ. Physiol. 2012, 302, H2190–H2210.
  53. Song, T.; Hao, Q.; Zheng, Y.M.; Liu, Q.H.; Wang, Y.X. Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2015, 309, L1455–L1466.
  54. Wang, Y.X.; Zheng, Y.M.; Mei, Q.B.; Wang, Q.S.; Collier, M.L.; Fleischer, S.; Xin, H.B.; Kotlikoff, M.I. FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells. Am. J. Physiol. Cell Physiol. 2004, 286, C538–C546.
  55. Montaño, L.M.; Flores-Soto, E.; Reyes-García, J.; Díaz-Hernández, V.; Carbajal-García, A.; Campuzano-González, E.; Ramírez-Salinas, G.L.; Velasco-Velázquez, M.A.; Sommer, B. Testosterone induces hyporesponsiveness by interfering with IP3 receptors in guinea pig airway smooth muscle. Mol. Cell. Endocrinol. 2018, 473, 17–30.
  56. Romero-Martínez, B.S.; Montaño, L.M.; Solís-Chagoyán, H.; Sommer, B.; Ramírez-Salinas, G.L.; Pérez-Figueroa, G.E.; Flores-Soto, E. Possible Beneficial Actions of Caffeine in SARS-CoV-2. Int. J. Mol. Sci. 2021, 22, 5460.
  57. Deshpande, D.A.; Wang, W.C.H.; Mcilmoyle, E.L.; Robinett, K.S.; Schillinger, R.M.; An, S.S.; Sham, J.S.K.; Liggett, S.B. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat. Med. 2010, 16, 1299–1304.
  58. Reuquén, P.; Oróstica, M.L.; Rojas, I.; Díaz, P.; Parada-Bustamante, A.; Orihuela, P.A. Estradiol increases IP3 by a nongenomic mechanism in the smooth muscle cells from the rat oviduct. Reproduction 2015, 150, 331–341.
  59. Marino, M.; Pallottini, V.; Trentalance, A. Estrogens cause rapid activation of IP3-PKC-α signal transduction pathway in HEPG2 cells. Biochem. Biophys. Res. Commun. 1998, 245, 254–258.
  60. Ekstein, J.; Nasatzky, E.; Boyan, B.D.; Ornoy, A.; Schwartz, Z. Growth-plate chondrocytes respond to 17β-estradiol with sex-specific increases in IP3 and intracellular calcium ion signalling via a capacitative entry mechanism. Steroids 2005, 70, 775–786.
  61. Le Mellay, V.; Grosse, B.; Lieberherr, M. Phospholipase C β and membrane action of calcitriol and estradiol. J. Biol. Chem. 1997, 272, 11902–11907.
  62. Micevych, P.; Soma, K.K.; Sinchak, K. Neuroprogesterone: Key to estrogen positive feedback? Brain Res. Rev. 2008, 57, 470–480.
  63. Kirkwood, K.L.; Homick, K.; Dragon, M.B.; Bradford, P.G. Cloning and characterization of the type I inositol 1,4,5-trisphosphate receptor gene promoter. Regulation by 17β-estradiol in osteoblasts. J. Biol. Chem. 1997, 272, 22425–22431.
  64. Tomás, J.; Santos, C.R.A.; Duarte, A.C.; Maltez, M.; Quintela, T.; Lemos, M.C.; Gonçalves, I. Bitter taste signaling mediated by Tas2r144 is down-regulated by 17β-estradiol and progesterone in the rat choroid plexus. Mol. Cell. Endocrinol. 2019, 495, 110521.
  65. Sommer, B.; Flores-Soto, E.; Gonzalez-Avila, G. Cellular Na+ handling mechanisms involved in airway smooth muscle contraction (Review). Int. J. Mol. Med. 2017, 40, 3–9.
  66. DiPolo, R.; Beaugé, L. Sodium/calcium exchanger: Influence of metabolic regulation on ion carrier interactions. Physiol. Rev. 2006, 86, 155–203.
  67. Philipson, K.D.; Nicoll, D.A. Sodium-calcium exchange: A molecular perspective. Annu. Rev. Physiol. 2000, 62, 111–133.
  68. Lytton, J. Na+/Ca2+ exchangers: Three mammalian gene families control Ca2+ transport. Biochem. J. 2007, 406, 365–382.
  69. Algara-Suárez, P.; Mejía-Elizondo, R.; Sims, S.; Saavedra-Alanis, V.; Espinosa-Tanguma, R. The 1.3 isoform of Na+-Ca2+ exchanger expressed in guinea pig tracheal smooth muscle is less sensitive to KB-R7943. J. Physiol. Biochem. 2010, 66, 117–125.
  70. Janssen, L.J.; Walters, D.K.; Wattie, J. Regulation of i in canine airway smooth muscle by Ca2+-ATPase and Na+/Ca2+ exchange mechanisms. Am. J. Physiol. 1997, 273, L322–L330.
  71. Wen, J.; Meng, X.; Xuan, B.; Zhou, T.; Gao, H.; Dong, H.; Wang, Y. Na+/Ca2+ Exchanger 1 in Airway Smooth Muscle of Allergic Inflammation Mouse Model. Front. Pharmacol. 2018, 9, 1471.
  72. Xu, H.; Zhao, P.; Zhang, W.-J.; Qiu, J.-Y.; Tan, L.; Liu, X.-C.; Wang, Q.; Luo, X.; She, Y.-S.; Zang, D.-A.; et al. Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle. Cell. Physiol. Biochem. 2018, 47, 1546–1555.
  73. Sathish, V.; Delmotte, P.F.; Thompson, M.A.; Pabelick, C.M.; Sieck, G.C.; Prakash, Y.S. Sodium-calcium exchange in intracellular calcium handling of human airway smooth muscle. PLoS ONE 2011, 6, e23662.
  74. Rahman, M.; Inman, M.; Kiss, L.; Janssen, L.J. Reverse-mode NCX current in mouse airway smooth muscle: Na+ and voltage dependence, contributions to Ca2+ influx and contraction, and altered expression in a model of allergen-induced hyperresponsiveness. Acta Physiol. 2012, 205, 279–291.
  75. Kim, K.; Lee, D.; Ahn, C.; Kang, H.Y.; An, B.S.; Seong, Y.H.; Jeung, E.B. Effects of estrogen on esophageal function through regulation of Ca2+-related proteins. J. Gastroenterol. 2017, 52, 929–939.
  76. Chu, S.H.; Goldspink, P.; Kowalski, J.; Beck, J.; Schwertz, D.W. Effect of estrogen on calcium-handling proteins, β-adrenergic receptors, and function in rat heart. Life Sci. 2006, 79, 1257–1267.
  77. Sims, C.; Reisenweber, S.; Viswanathan, P.C.; Choi, B.R.; Walker, W.H.; Salama, G. Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2. Circ. Res. 2008, 102, e86–e100.
  78. Chen, G.; Yang, X.; Alber, S.; Shusterman, V.; Salama, G. Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen. J. Physiol. 2011, 589, 1061–1080.
  79. Kravtsov, G.M.; Kam, K.W.; Liu, J.; Wu, S.; Wong, T.M. Altered Ca2+ handling by ryanodine receptor and Na+-Ca2+ exchange in the heart from ovariectomized rats: Role of protein kinase A. Am. J. Physiol. Cell Physiol. 2007, 292, C1625–C1635.
  80. Yang, H.Y.; Firth, J.M.; Francis, A.J.; Alvarez-Laviada, A.; MacLeod, K.T. Effect of ovariectomy on intracellular Ca2+ regulation in guinea pig cardiomyocytes. Am. J. Physiol.-Heart Circ. Physiol. 2017, 313, H1031–H1043.
  81. Sugishita, K.; Su, Z.; Li, F.; Philipson, K.D.; Barry, W.H. Gender influences i during metabolic inhibition in myocytes overexpressing the Na+-Ca2+ exchanger. Circulation 2001, 104, 2101–2106.
  82. Cross, H.R.; Lu, L.; Steenbergen, C.; Philipson, K.D.; Murphy, E. Overexpression of the Cardiac Na+/Ca2+ Exchanger Increases Susceptibility to Ischemia/Reperfusion Injury in Male, but Not Female, Transgenic Mice. Circ. Res. 1998, 83, 1215–1223.
  83. Sánchez, J.C.; López-Zapata, D.F.; Francis, L.; De Los Reyes, L. Effects of estradiol and IGF-1 on the sodium calcium exchanger in rat cultured cortical neurons. Cell. Mol. Neurobiol. 2011, 31, 619–627.
  84. Jeffs, G.J.; Meloni, B.P.; Bakker, A.J.; Knuckey, N.W. The role of the Na+/Ca2+ exchanger (NCX) in neurons following ischaemia. J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas. 2007, 14, 507–514.
  85. Chen, Y.F.; Cao, J.; Zhong, J.N.; Chen, X.; Cheng, M.; Yang, J.; Gao, Y.D. Plasma membrane Ca2+-ATPase regulates Ca2+ signaling and the proliferation of airway smooth muscle cells. Eur. J. Pharmacol. 2014, 740, 733–741.
  86. Varga, K.; Hollósi, A.; Pászty, K.; Hegedűs, L.; Szakács, G.; Tímár, J.; Papp, B.; Enyedi, Á.; Padányi, R. Expression of calcium pumps is differentially regulated by histone deacetylase inhibitors and estrogen receptor alpha in breast cancer cells. BMC Cancer 2018, 18, 1029.
  87. El-Beialy, W.; Galal, N.; Deyama, Y.; Yoshimura, Y.; Suzuki, K.; Tei, K.; Totsuka, Y. Effects of Estrogen on PMCA 2 and 4 in Human Fibroblast-like Synovial Cells and Mouse Macrophage-like Cells. Endocr. J. 2010, 57, 93–97.
  88. Dick, I.M.; Liu, J.; Glendenning, P.; Prince, R.L. Estrogen and androgen regulation of plasma membrane calcium pump activity in immortalized distal tubule kidney cells. Mol. Cell. Endocrinol. 2003, 212, 11–18.
  89. Khariv, V.; Acioglu, C.; Ni, L.; Ratnayake, A.; Li, L.; Tao, Y.-X.; Heary, R.F.; Elkabes, S. A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain. Sci. Rep. 2018, 8, 17260.
  90. Bobe, R.; Bredoux, R.; Corvazier, E.; Andersen, J.P.; Clausen, J.D.; Dode, L.; Kovács, T.; Enouf, J. Identification, Expression, Function, and Localization of a Novel (Sixth) Isoform of the Human Sarco/Endoplasmic Reticulum Ca2+ ATPase 3 Gene. J. Biol. Chem. 2004, 279, 24297–24306.
  91. Mahn, K.; Hirst, S.J.; Ying, S.; Holt, M.R.; Lavender, P.; Ojo, O.O.; Siew, L.; Simcock, D.E.; Mcvicker, C.G.; Kanabar, V.; et al. Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma. Proc. Natl. Acad. Sci. USA 2009, 106, 10775–10780.
  92. Prakash, Y.S.; Sathish, V.; Thompson, M.A.; Pabelick, C.M.; Sieck, G.C. Asthma and sarcoplasmic reticulum Ca2+ reuptake in airway smooth muscle. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2009, 297, L794.
  93. Carbajal, V.; Vargas, M.H.; lores-Soto, E.F.; Martínez-Cordero, E.; Bazán-Perkins, B.; Montaño, L.M. LTD4 induces hyperresponsiveness to histamine in bovine airway smooth muscle: Role of SR-ATPase Ca2+ pump and tyrosine kinase. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2005, 288, L84–L92.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Physiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Bianca S. Romero-Martínez
,
Bettina Sommer
,
Héctor Solís-Chagoyán
,
Eduardo Calixto
,
Arnoldo Aquino-Gálvez
,
Ruth Jaimez
,
Juan C. Gomez-Verjan
,
Georgina González-Avila
,
Edgar Flores-Soto
,
Luis M. Montaño
View Times: 236
Revisions: 2 times (View History)
Update Date: 15 May 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback