Molecular Machinery Involved in Brain-Derived Nerve Factor Release: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Ruben Deogracias Pastor.

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion.

  • BDNF
  • proBDNF
  • Ca2+
  • expression
  • nerve cells
  • neurotrophins

1. Introduction

Brain-derived nerve factor (BDNF) secretion is tightly controlled by different stimuli but also by different transmembrane and intracellular proteins that are implicated in raising cytoplasmic Ca2+ levels and responding to this elevation. Researchers will describe most of the known proteins (Table 1).
Table 1.
Proteins involved in BDNF secretion.
Protein Effect Cells BDNF Source References
ARMS/Kidins220 − Neurons synthesized [94,105][1][2]
CAPS2 + Neurons synthesized [110,125,146,147][3][4][5][6]
mGluR + Neurons/Astrocytes endocytosed/recycled [80,95,97][7][8][9]
Munc-18 + Neurons synthesized [148,149][10][11]
PKA + Neurons/Glial cells   [150][12]
PKG −/+ Neurons   [151,152,153][13][14][15]
PLC –/+ Neurons/Astrocytes synthesized

endocytosed/recycled		 [80,95,97][7][8][9]
Rab3a/Rim1 + Neurons/Astrocytes synthesized

endocytosed/recycled		 [96,154,155,156,157][16][17][18][19][20]
SNAP25 + Neurons synthesized [158][21]
SNAP47 + Neurons synthesized [158][21]
Synaptobrevin2 + Neurons synthesized

endocytosed/recycled		 [158][21]
Synaptotagmin4 – Neurons synthesized [105,119,159][2][22][23]
Synaptotagmin6 /complexin 1 + Neurons endocytosed/recycled [159][23]
Trk receptors + Neurons synthesized [104,105,108][2][24][25]
Vamp3 + Astrocytes endocytosed/recycled [160][26]

2. Trk Neurotrophin Receptors

Neurotrophins bind to their corresponding Trk receptor, nerve growth factor (NGF) to TrkA, BDNF and neurotrophin-4 (NT-4) to TrkB, and neurotrophin-3 (NT-3) to TrkC [30,161][27][28]. The role of neurotrophins through the activation of Trk receptors in the regulation of BDNF release was described in two pioneer studies carried out in primary neurons and PC12 cells [104,108][24][25]. This secretion is dependent on Ca2+ release from intracellular stores [108][25] and phospholipase C (PLC) [80][7]. Other authors have observed that treatment of cortical/hippocampal slices and dorsal root ganglion neurons with NT-3 or NT-4 and NGF, respectively, led to BDNF release [105][2]. In addition, the role of TrkB.T1 receptor in the release of previously internalized BDNF from astrocytes has been described [142][29]. TrkB.T1 knockout mice show that the truncated receptor participates in several neurological disorders such amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson´s disease in which BDNF levels are also altered (reviewed by Tessarollo and Yanpallewar, 2022) [162][30]. These studies point out that neurotrophin receptor-regulated BDNF secretion may provide a positive feedback mechanism for physiological functions such as selective stabilization of synaptic connections, potentiation of synaptic transmission, and memory formation. However, an impairment of BDNF availability is observed in different diseases when neurotrophin receptors are altered.

3. ARMS/Kidins220

ARMS/Kidins220 (ARMS hereinafter) is a transmembrane scaffold protein with pleiotropic functions in the nervous system and other systems [163][31]. The gene coding for ARMS was cloned independently as a protein kinase D (PKD) substrate [164][32] and as a downstream target of the signaling mediated by neurotrophins and ephrins [165][33]. ARMS structure is composed of eleven ankyrin repeats, a Walker A and B domain, four transmembrane regions, a proline-rich domain, a sterile-alfa motif (SAM), a kinesin light chain (KLC)-interacting motif (KIM), and a PDZ-binding motif. ARMS interacts with multiple proteins within its multiple domains acting as a signaling platform [163][31].
The first article implicating ARMS in secretion was related with neurotensin release downstream of PKD [166][34]. The authors reported a positive role of ARMS in neurotensin secretion from BON cells downstream of PKD signaling pathway in response to phorbol esters, in which ARMS seems to regulate neurotensin vesicle transport to the plasma membrane [166][34]. The involvement of ARMS in secretion in the nervous system comes from the regulated secretion in the PC12 neuronal cell line in response to NGF [167][35]. However, in this case it was reported that ARMS plays a negative role, since reducing and increasing its levels resulted in increased and decreased secretion, respectively. Mechanistically, ARMS was acting together with synembryn, a protein previously involved in the neurotransmitter release at the neuromuscular junction in C. elegans [168][36], and upstream of Gαq, Trio, and Rac proteins [168][36]. Interestingly, proliferating PC12 cells showed high levels of ARMS with very low NGF-mediated secretion, whereas differentiated PC12 cells showed low levels of ARMS and high NGF-mediated secretion, and manipulation of ARMS levels demonstrated its negative effect on release [167][35]. Furthermore, the role of ARMS in secretion was studied in CNS and PNS in two different studies looking at regulated BDNF secretion. In the first study, López-Benito and collaborators demonstrated that ARMS negatively regulates BDNF release in response to NT-3, NT-4, and depolarization in vitro in cultured cortical neurons [105][2]. As a result of knocking down ARMS levels in vivo both in the cortex and hippocampus, there is an accumulation of BDNF in the striatum, a region that does not express BDNF but that receives it from the cortex and hippocampus. Mechanistically, the ARMS effect on BDNF release depends on the regulation of Syt4 levels [105][2], a protein which has been previously observed to modulate BDNF secretion (see below) [119][22]. In the second study, knocking down ARMS in TrkA-expressing cells resulted in an enhanced release of BDNF from dorsal root ganglion neurons in the spinal cord in response to capsaicin injection [94][1]. As a result, ARMS modulates thermal and inflammatory nociception, effects of which directly depend on the presence of BDNF. Importantly, ARMS protein levels are downregulated by noxious stimuli, which trigger neuronal activity [94][1]. Altogether, these studies point to a seminal role of ARMS on functions directly dependent on BDNF secretion.
The relevance of ARMS controlling BDNF release is palpable in physiological and pathological conditions. It is demonstrated that ARMS influences synaptic activity by controlling basal synaptic transmission [169][37] and enhances LTP in heterozygous ARMS mice [170][38]. Since LTP depends on BDNF secretion [171[39][40],172], strict control of ARMS protein quantity is required. ARMS levels are regulated by calpains [170[38][41],173], which are a family of evolutionarily conserved Ca2+-dependent cysteine proteases that function in numerous processes including synaptic plasticity and neuronal survival/degeneration [174,175][42][43]. The effect on LTP is linked to calpain-mediated cleavage of ARMS [170][38], a phenomenon occurring in response to neuronal activity. Calpain-dependent proteolysis is ideal for ARMS degradation because its enzymatic activity is induced by increases in intracellular Ca2+ levels in response to neuronal activity. Since ARMS regulates BDNF secretion, LTP induction, and modulates functions of GluA1 and NMDARs [169[37][44],176], the regulation on ARMS levels has a direct impact on neuronal maturation and synaptic plasticity [169,170,177][37][38][45]. It has been reported that ARMS is also involved in the development of brain pathological conditions. For example, it has been observed that in two different mouse models of Huntington’s disease (HD) increased levels of ARMS caused a deficit in the regulated secretion of BDNF [105][2]. In addition, the hippocampus and prefrontal cortex (PFC) of HD patients [105][2] and the temporal cortex of Alzheimer´s Disease (AD) patients [178][46] display elevated ARMS levels. Altogether, these studies suggest that ARMS is a key protein in the regulation of the secretion of BDNF both in physiological and pathological conditions in the nervous system.

4. PKG

Protein kinase G (PKG) isozymes belong to the family of serine/threonine kinases that are activated by cGMP and are homologous to cAMP-dependent-protein kinase A (PKA) [179][47]. The involvement of PKG in BDNF secretion was originally reported in cultured hippocampal neurons expressing exogenous BDNF [151][13]. In response to nitric oxide (NO), cGMP levels are raised activating PKG, which in turn prevents Ca2+ release from inositol 1,4,5-triphosphte-sensitive stores leading to a rapid down-regulation of BDNF secretion [151][13]. Another report indicates that exogenous NO abolishes BDNF release from in vitro cultures of newborn rat nodose ganglion neurons stimulated with single electrical pulses, but this effect seems not to involve PKG [152][14]. Recently, it has been reported that in spinal terminals of nociceptors, presynaptic NMDARs activation in response to tissue inflammation enhances BDNF secretion. This effect is dependent on prolonged Ca2+ elevation and PKG activation leading to synaptic potentiation in the inflammatory state [153][15]. Although PKG activation evokes opposite effects of BDNF secretion in different systems, PKG signaling pathway represents a signaling mechanism by which neurons can modulate BDNF secretion.

5. Rab3a-Rim1

Rab3 is a small GTPase localized on membranes of DCVs [180][48]. This protein acts together with its neuronal effector, Rab3 interacting molecule (Rim1), in the release of neuropeptides and neurotrophins [155][18]. In astrocytes, Rab3a is involved in the docking of BDNF vesicles on the plasma membrane, which is impaired by mutant huntingtin [154][17], whereas in neurons, DCV exocytosis is undetectable upon RIM1/2 deletion [155][18]. Rab3 plays a crucial role in the presynaptic, but not postsynaptic, component of BDNF-induced synaptic charge [156[19][20],157], an effect that requires Rab3/Rim1 to activate proline-directed Ser/Thr protein kinases [96][16]. Altogether, these studies indicate that Rab3a participates in docking DCVs containing BDNF, which participate on synaptic transmission.

6. Munc18

Munc18-1 is a member of the Sec1/Munc18 (SM) family of proteins playing fundamental roles in membrane trafficking [181][49]. It has been implicated in the synaptic vesicle docking, priming, and fusion, functions that depend, at least in part, on its capacity to bind the neuronal SNAREs [182][50]. Munc18-1 knockout mice die at birth and show massive neurodegeneration [183][51]. Munc18-1-deficient hippocampal neurons displayed reduced BDNF secretion [148][10], and BDNF application on these neurons delays their death and rescues their severe synaptic dysfunctions [148,149,184][10][11][52]. The impaired neuropeptide secretion may explain aspects of the behavioral and neurodevelopmental phenotypes that were observed in Munc18-1 heterozygous mice [149][11]. Moreover, BDNF/TrkB signaling in response to synaptic activity at the neuromuscular junction prevents Munc18-1 phosphorylation, preventing its binding to syntaxin [185][53]. All together, these data suggest a role of Munc18-1 in BDNF secretion and the presence of a positive feedback loop between BDNF/TrkB signaling and Munc18-1 function.

7. CAPS2

Ca2+-dependent activator protein for secretion (CAPS2) is an 1803 amino acid protein that has structural features including a dynactin1 interaction domain (DID), a C2 domain, a PH domain, and the Munc13-1-homologous domain (MHD) containing a syntaxin-interacting domain. CAPS2 shares 70.4% amino acid identity with CAPS1 and have different splice variants [110,146][3][5]. CAPS2 is enriched in vesicular structures of the presynaptic parallel fiber terminals of cerebellar granule cells mediating the depolarization-dependent release of NT-3 and BDNF that regulates cell differentiation and survival during cerebellar development [110,146][3][5]. In addition, CAPS2 expression in hippocampal GABAergic neurons regulates BDNF secretion, development of hippocampal GABAergic neurons and their synapses without affecting excitatory hippocampal neurons [125][4]. CAPS2 knockout mice exhibited impaired activity-dependent BDNF secretion, reduced late-phase long-term potentiation at CA3–CA1 synapses, decreased hippocampal theta oscillation frequency, and increased anxiety-like behavior [110,125,147][3][4][6]. In addition, CAPS2 knockout mice show autistic-like cellular and behavioral phenotypes, and, in autistic patients, an aberrant alternatively spliced CAPS2 mRNA lacking the exon 3 was identified [110][3]. This exon codes for a region involved in the binding to dynactin 1 motor protein and proper localization of CAPS2 in axons [110][3]. Mice with the exon 3 deleted showed a reduction in BDNF release from axons and autistic-like behavior [123][54]. The deficits in CAPS2, or its splicing variant, in the regulation of BDNF secretion may be responsible for the development and maturation of synapses and in the balance between the inhibitory and excitatory systems. Altogether, CAPS2 seems to be responsible for BDNF secretion, and dysregulation of the protein provokes deficits in brain development and autism-related behaviors in mice and patients.

8. Synaptotagmin 4 and Synaptotagmin 6

Synaptotagmin 4 (Syt4) belongs to the synaptotagmin family of proteins [186][55]. Syt4 harbors an aspartate-to-serine substitution in a Ca2+ coordination site of the C2A domain and, therefore, is unable to bind Ca2+. Syt4 binds to SNARE proteins but fails to bind more avidly to SNAREs or to penetrate membranes in response to Ca2+. Thus, Syt4 can join the fusion complex but prevents an essential fusion step limiting exocytosis [181][49]. Syt4 is mainly expressed in brain and neuroendocrine tissues at relatively low levels, but it is induced by neuronal depolarization, seizures, and psychoactive drugs [187,188,189,190,191][56][57][58][59][60]. Syt4 is localized to BDNF-containing vesicles in hippocampal neurons, and its role inhibiting BDNF release at both axons and dendrites was demonstrated using knockout and overexpressing hippocampal neurons [119][22]. This effect was at the postsynaptic site of BDNF release affecting indirectly at the rate of synaptic vesicle exocytosis from presynaptic terminals. In addition, Syt4 knockout mice showed enhanced TBS-mediated LTP, which depended entirely on disinhibition of BDNF release [119][22]. Furthermore, Syt4 seems to work together with ARMS since depletion of ARMS levels abolished the inhibitory effect of Syt4 overexpression on BDNF secretion [105][2]. Therefore, Syt4 seems to be instrumental for the control of BDNF release and LTP induction.
It is known that hippocampal neurons could recycle BDNF after endocytosis for activity-dependent secretion, and this BDNF could replace its new synthesis required for the late phase of LTP [82][61]. Wong and collaborators reported that another member of the synaptotagmin family, synaptotagmin 6 (Syt6), promotes activity-dependent exocytosis of BDNF-containing endosomes [159][23]. Specific down-regulation of Syt6 abolished activity-driven release of endocytosed BDNF at postsynaptic sites [159][23]. In addition, complexin1, which activates and clamps vesicular exocytosis interacting with SNARE proteins, is required for activity-dependent exocytosis of BDNF at postsynaptic sites, but at the same time it prevents spontaneous exocytosis of docked endosomes [159][23]. Additionally, the protein Vamp3 has been recently implicated in BDNF release from endocytosed BDNF [160][26]. Thus, using different proteins, endocytosed BDNF can be stored with the activity-dependent releasable pool required for LTP maintenance.

9. SNARE Proteins

SNARE complexes are formed primarily by synaptobrevin/VAMP2 (Syb2), SNAP25, and syntaxin1 and are seminal for presynaptic release of synaptic neurotransmitter vesicles overcoming the energy barrier for their fusion with the plasma membrane [183][51]. In addition, Shimojo and collaborators found that Syb2 and SNAP25 are involved in BDNF release in cortical neurons together with SNAP47 [158][21]. Previously, it was reported that Syb2 and SNAP25 colocalized with CAPS2 [192][62]. Thus, SNARE protein complexes also participate in BDNF secretion.

10. mGluR

The metabotropic glutamate receptor (mGluR) family is composed of three groups based on the sequence homology and G-protein coupling, correspondingly mGluR1 and 5 (Group I), mGluR2 and 3 (Group II), and Group III, including mGluRs 4, 6, 7, and 8. [193][63]. The main intracellular transduction cascade activated by group I mGluRs, coupled to Gq/G11, is the phospholipase C pathway. This activation results in the generation of inositol 1,4,5-trisphosphate (IP3) and Ca2+ mobilization from intracellular stores [194][64]. mGluRI-dependent activation of PLC induces BDNF release in hippocampal neurons [80][7], in astrocytes [95][8] and in oligodendrocytes [97][9].

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