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Emerging evidence for specific neuronal functions of auxiliary calcium channel ??? subunits.

ABSTRACT: In nerve cells the ubiquitous second messenger calcium regulates a variety of vitally important functions including neurotransmitter release, gene regulation, and neuronal plasticity. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which consist of a heteromultimeric complex of a pore forming ??, and the auxiliary ? and ??? subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached ??? subunits (???-1 to ???-4), out of which three isoforms (???-1 to -3) are strongly expressed in the central nervous system. Over the years a wealth of studies has demonstrated the classical role of ??? subunits in channel trafficking and calcium current modulation. Recent studies in specialized neuronal cell systems propose roles of ??? subunits beyond the classical view and implicate ??? subunits as important regulators of synapse formation. These findings are supported by the identification of novel human disease mutations associated with ??? subunits and by the fact that ??? subunits are the target of the anti-epileptic and anti-allodynic drugs gabapentin and pregabalin. Here we review the recently emerging evidence for specific as well as redundant neuronal roles of ??? subunits and discuss the mechanisms for establishing and maintaining specificity.

SUBMITTER: Geisler S

PROVIDER: S-EPMC4487825 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Emerging evidence for specific neuronal functions of auxiliary calcium channel α₂δ subunits.

Geisler Stefanie S Schöpf Clemens L CL Obermair Gerald J GJ

General physiology and biophysics 20141211 2

In nerve cells the ubiquitous second messenger calcium regulates a variety of vitally important functions including neurotransmitter release, gene regulation, and neuronal plasticity. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which consist of a heteromultimeric complex of a pore forming α₁, and the auxiliary β and α₂δ subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached α₂δ subunits (α₂δ-1 to α₂δ-4), out of which three iso ...[more]

PMID: 25504062

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Project description:VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on α2δ1 knockdown. Overexpression of α2δ3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonaloutgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.SIGNIFICANCE STATEMENT The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that, in early development, auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses, and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development, α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels.

Project description:P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 ?1 subunit and the auxiliary ?2?-2 and ?4 subunits. ?4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat ?4b cDNA. Heterologously expressed wild-type ?4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the ?4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, ?4b and ?4b-L125P augmented the calcium current amplitudes, however, ?4b-L125P failed to stably complex with ?1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of ?4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype ?4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of ?4b in cultured myotubes and hippocampal neurons. While binding of ?4b to the known interaction partner PPP2R5D (B56?) was not affected by the mutation, complex formation between ?4b-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of ?4b.

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Emerging evidence for specific neuronal functions of auxiliary calcium channel ??? subunits.

Publications

Emerging evidence for specific neuronal functions of auxiliary calcium channel α₂δ subunits.

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