Figure 1. Activation of the TRPV1 ligand-gated ion channel causes Ca²⁺ influx into the cytosol and influences the balance between proliferation and apoptosis. Apoptotic signaling occurs through the cytosol, mitochondria, ER, and the nucleus. In contrast, the proliferative effects of TRPV1 are mediated by the activation of other cell membrane receptors, ER signaling, and cytosolic protein signaling cascades. The proliferative, proapoptotic mitochondrial, proapoptotic ER, and proapoptotic nuclear signaling mechanisms are highlighted in the colored boxes, and specified in Figure 2 Figure 3 Figure 4 Figure 5, respectively.

Figure 2. TRPV1 induces proliferation through Ca²⁺ entry, ATP release and membrane P2Y purinoceptor 2 (P2Y2) activation, and the transactivation of epidermal growth factor receptor (EGFR). Elevated [Ca²⁺]_i and ATP-P2Y2 binding upregulate intracellular inositol triphosphate (IP₃) via phospholipase C (PLC); IP₃ opens store-operated channels (SOC) and thereby causes Ca²⁺ release from the ER. Activated P2Y2 receptors also begin the phosphoinositide-3-kinase (PI3K)/Akt pathway, a kinase signaling cascade that ultimately activates Akt. TRPV1 additionally transactivates EGFR; this prompts Ras/Raf/MAPK-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling, which upregulates ERK 1/2 mitogen-activated protein kinases (MAPK). Akt and ERK 1/2 MAPK promote proliferation through nuclear activity.

Figure 3. TRPV1 induces mitochondrial dysfunction through Ca²⁺ and Na⁺ entry, membrane depolarization, reactive oxygen species (ROS) production, and the release of cytochrome c and apoptosis-inducing factor (AIF). Initial Ca²⁺ and Na⁺ influx causes the hyperpolarization of the mitochondrial membrane, while consequent Ca²⁺ export through the permeability transition pore (PTP) and active Ca²⁺ removal via the Na⁺/Ca²⁺ exchanger (NCLX) depolarize the membrane. As inputs, downregulated intracellular glutathione  ([GSH]_i) and upregulated Bax arise from nuclear activity. Upon their release (driven by membrane depolarization), AIF translocates directly to the nucleus, cytochrome c participates in intracellular caspase 9 activation, and intracellular ROS (ROS_i) supports the activation of p38 MAPKs.

Figure 4. Cell membrane and ER TRPV1 activation promote ER stress through the modulation of [Ca²⁺]_ER, activation of various kinases, the upregulation of nuclear transcription factors, and the release of c-Jun N-terminal kinase (JNK) into the cytosol. TRPV1 proteins localized to the ER membrane contribute only to protein signaling within the ER, while TRPV1 channels in the cell membrane promote both [Ca²⁺]_i and protein signaling. Initial Ca²⁺ entry into the ER occurs through the sarco/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) pump, which is eventually blocked, causing net Ca²⁺ export via the ryanodine receptor 2 (RyR2) channels. Glucose regulated protein 78 (GRP78) upregulation and Bcl-2 downregulation, as inputs, arise from nuclear activity. MAPK is both an input and output of ER stress, as it is upregulated via both mitochondrial activity and JNK. Activating transcription factors 4 (ATF4) and 6 (ATF6) and X-box binding protein 1 (XBP1) are transcription factors that constitute the downstream nuclear targets of ER stress; ATF4, in particular, feeds back to the ER by upregulating GRP78.

Figure 5. Pro-apoptotic processes induced by TRPV1 localized in the nucleus. The nuclear component of ER stress occurs as ATF4, ATF6, and XBP1 are activated by ER stress and upregulate GADD153, which in turn downregulates Bcl-2 protein production. The upregulation of GRP78 by ATF4 feeds back to and enhances ER stress. The cytosolic activation of the ATM serine-threonine kinase by TRPV1 protein signaling and calcineurin by elevated [Ca²⁺]_i promote the nuclear transcription factors E2F1, MYC, and NFAT2, which upregulate p53. The precise mechanism through which TRPV1 activates ATM remains unclear. p53 upregulates the apoptotic mediators Bax, p16, and p21, which activate caspase 9 and 3. Activated caspases translocate from the cytosol to the nucleus, where they mediate DNA fragmentation and condensation.

Abbreviations: ATP, Adenosine TriPhosphate; AIF, Apoptosis Inducing Factor; Akt, Akt serine-threonine protein kinase; ASK1, Apoptosis Signal-regulating Kinase 1; ATF4, Activating Transcription Factor 4; ATF6, Activating Transcription Factor 6; ATM, ATM serine-threonine kinase; Bax, Bcl-2 associated x protein; Bcl-2, B-cell lymphoma 2; BID, BH3 Interacting-domain Death agonist; E2F1, E2F transcription factor 1; EGFR, Epidermal Growth Factor Receptor; eIF2, eukaryotic Initiation Factor 2; ERK, Extracellular signal-Regulated Kinase; GADD153, DNA Damage-Inducible Transcript 3; GRP78, Glucose Regulated Protein 78; [GSH]_i, intracellular glutathione; [GSH]_m, mitochondrial glutathione; IP₃, Inositol triPhosphate; IRE1, Inositol-Requiring Enzyme 1; JNK, c-Jun N-terminal Kinase; MAPK, Mitogen Activated Protein Kinase; MCU, Mitochondrial Ca²⁺ Uniporter; MEK, MAPK-ERK Kinase; MMP, Mitochondrial Membrane Potential; MYC, Myc proto-oncogene; NCLX, Na⁺/Ca²⁺ exchanger; NFAT2, Nuclear Factor of Activated T-cells 2; P2Y2, P2Y purinoceptor 2; PDK, Phosphoinositide-Dependent Kinase; PERK, PKR-like Endoplasmic Reticulum Kinase; PI3K, PhosphoInositide-3-Kinase; PKC, Protein Kinase C; PLC, PhosphoLipase C; PTP, Permeability Transition Pore; Raf, Rapidly accelerated fibrosarcoma; Ras, Rat sarcoma; ROS, Reactive Oxygen Species; ROSi, intracellular Reactive Oxygen Species; ROS_m, mitochondrial Reactive Oxygen Species; RyR2, Ryanodine Receptor 2; SERCA, Sarco/Endoplasmic Reticulum Ca²⁺ ATPase; SOC, Store-Operated Channel; Src, proto-oncogene tyrosine-protein kinase Src; TRPV1, Transient Receptor Potential Vanilloid 1; VDAC, Voltage Dependent Anion Channel; XBP1, X-box Binding Protein 1.