Associate editor: M.W. QuickTransient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: Potential implications for Rett syndrome
Introduction
The neurotrophins are a family of secretory proteins involved in neuronal survival and differentiation during early brain development (Barde, 1989). These proteins are released from target tissues and serve as chemoattractants for growing undifferentiated nerve cell processes, that is, neurites, with the consequence being the formation of functional synapses. Furthermore, neurotrophins play a crucial role as survival signals, given that there is only a limited amount available for release as postulated in the neurotrophin hypothesis (Levi-Montalcini, 1987). The growing neurites compete for neurotrophins, hence, those that receive the proteins will continue to grow and mature; however, those that do not will be pruned and die. In this way, the overabundance of neurons produced in early development is reduced to that which is necessary to innervate all target tissues (Oppenheim, 1991). Recently, however, the family of neurotrophic factors, in general, and brain-derived neurotrophic factor (BDNF), in particular, has emerged as potent modulators of activity-dependent synaptic plasticity in the mature central nervous system (CNS). It is essential, then, to elucidate the signaling mechanisms and downstream targets utilized by neurotrophins so that these newly recognized functions might be better understood.
Neurotrophins exert their varied actions through the activation of intracellular signaling cascades via two distinctive transmembrane receptors, the tropomyosin-related kinase (Trk) family of receptor protein kinases and the pan-neurotrophin receptor 75 kD (p75NTR) receptor (Barbacid, 1993). A significant amount of research has uncovered many facets of neurotrophin signaling, however, there is still plenty to be learned. This is clearly demonstrated by the recent, unexpected finding that transient receptor potential channel (TRPC) activation is a downstream consequence of BDNF signaling in particular. The transient receptor potential (TRP) family of ion channels was originally described in Drosophila photoreceptors, and their mammalian homologues are currently implicated in a variety of cellular functions, ranging from sensory transduction (e.g., temperature, touch, pain, osmolarity, pheromone, taste) to modulation of the cell cycle (Montell et al., 2002, Clapham, 2003). Members of the TRP ion channel family also play a critical role in capacitative Ca2+ entry (Birnbaumer et al., 1996), a relatively unexplored form of sustained Ca2+ signaling neurons (Putney, 2003). Intriguingly, TRPC-mediated Ca2+ elevations may underlie the morphological sculpting of neuronal dendrites by BDNF, that is, an increase in the density of dendritic spines, the site of ∼ 90% of excitatory synapses in the brain (Peters et al., 1991).
By focusing upon any one aspect of these signaling cascades, the ability to reveal a role for neurotrophins in disease states begins to materialize. Mutations and chromosomal aberrations causing mental retardation (MR) have consistently been associated with dendritic anomalies, including the morphology and density of dendritic spines (Fiala et al., 2002). Of these, Rett syndrome (RTT) is an X-linked neurodevelopmental disorder and the leading cause of severe MR in females, affecting one in 10,000–15,000 births worldwide (Neul & Zoghbi, 2004). Loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) have been recently identified in RTT patients (Amir et al., 1999). MeCP2 binds specifically to CpG-methylated DNA and is thought to inhibit gene transcription by recruiting co-repressor and histone deacetylase complexes and altering the structure of genomic DNA (Nan et al., 1998). One of the recently described targets of MeCP2 is the BDNF gene, suggesting that a deregulation of BDNF expression may be the cause of the structural anomalies observed in RTT patients, especially the reduced dendritic branching and loss of dendritic spines.
Section snippets
Neurotrophin signaling through tropomyosin-related kinase receptors
Four neurotrophins have been identified in mammals, and all are widely expressed in the CNS: nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) (Lewin & Barde, 1996). They exert their effects by binding to pan-neurotrophin p75NTR receptors, members of the tumor necrosis factor receptor superfamily, and to specific tyrosine kinase receptors, members of the trk family of proto-oncogenes related to insulin and epidermal growth factor receptors (Barbacid, 1993,
Does brain-derived neurotrophic factor cause calcium mobilization from intracellular stores?
One of the prominent signaling cascades activated by Trk neurotrophin receptors, the hydrolysis of phosphatidylinositol-4,5-biphosphate (PIP2) by activated PLC-γ leading to the formation of inositol-tris-phosphate (IP3) and subsequent Ca2+ mobilization from smooth endoplasmic reticulum (ER) through IP3 receptors (IP3R) (Berridge, 1998) is expected to cause Ca2+ elevations in neurons (Segal and Greenberg, 1996, Huang and Reichardt, 2003). This pathway converges on the same IP3R-containing Ca2+
Does brain-derived neurotrophic factor induce capacitative calcium entry?
In addition to well-established voltage- and ligand-gated mechanisms of Ca2+ influx in neurons (Berridge, 1998), Ca2+ entry associated with depletion of intracellular Ca2+ stores is beginning to emerge as a fundamental component of neuronal Ca2+ signaling. In non-excitable cells, the depletion of these stores activates plasma membrane channels often called store-operated channels (SOC), allowing Ca2+ entry for their replenishment. In both excitable (i.e., neurons and cardiac and skeletal muscle
Presynaptic effects: neurotransmitter release
Several of the multiple actions of BDNF in neuronal function are mediated by intracellular signaling cascades that are either dependent or highly sensitive to intracellular Ca2+ elevations, such as neurotransmitter release or short- and long-term synaptic plasticity. BDNF can contribute to neuronal Ca2+ homeostasis through direct or indirect actions on membrane depolarization at both presynaptic and postsynaptic sites. At the presynaptic level, BDNF enhances excitatory synaptic transmission by
Brain-derived neurotrophic factor, methyl-CpG-binding protein 2 and dendritic spine pathologies in Rett syndrome
Neurological disorders associated with MR are characterized by a prevalent deficit in cognitive function and adaptive behavior that range in phenotype severity and are often accompanied by specific symptoms. MR-associated disorders that have environmental, neurodegenerative or genetic origins have long been associated with structural anomalies of dendritic spines (Fiala et al., 2002). The pioneering studies by Huttenlocher, 1970, Huttenlocher, 1974, Marin-Padilla, 1972, Marin-Padilla, 1976, and
Conclusions
The intracellular signaling cascades activated by BDNF binding to TrkB receptors include several well-characterized protein kinases that target most of the routes of Ca2+ entry into hippocampal neurons, while the role of p75NTR signaling is only beginning to emerge. In addition to its strong presynaptic actions on quantal neurotransmitter release, the activation of a slowly developing depolarizing TRPC current associated with Ca2+ signals by BDNF is a likely mechanism for its modulation of
Acknowledgments
The work from the Pozzo-Miller laboratory discussed here was supported by NIH grants NS40593 (LP-M), P30-HD38985 (UAB Mental Retardation Research Center), the Evelyn F. McKnight Brain Research Foundation, and the Civitan International Foundation. LP-M is a McNulty Civitan Scientist. We would like to apologize in advance to the authors whose work was inadvertently omitted.
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2022, Neuroscience ResearchCitation Excerpt :BDNF-TrkB signaling has been reported to promote dendritic filopodial motility and synapse formation via the activation of PI3K (Luikart et al., 2008) and the BDNF-TrkB axis is essential for structural long-term potentiation (LTP) (Lai et al., 2012; Harward et al., 2016). Furthermore, it has been shown that BDNF contributes to the formation and maturation of spines (Tyler and Pozzo-Miller, 2003; Alonso et al., 2004; Amaral et al., 2007), although the underlying molecular mechanisms of such BDNF function has not been fully elucidated. Drebrin, an actin-binding protein that forms stable F-actin and is highly accumulated within dendritic spines (Shirao, 1995; Mikati et al., 2013; Koganezawa et al., 2017).
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