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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:As with other elements of the peripheral auditory system, spiral ganglion neurons display specializations that vary as a function of location along the tonotopic axis. Previous work has shown that voltage-gated K(+) channels and synaptic proteins show graded changes in their density that confers rapid responsiveness to neurons in the high frequency, basal region of the cochlea and slower, more maintained responsiveness to neurons in the low frequency, apical region of the cochlea. In order to understand how voltage-gated calcium channels (VGCCs) may contribute to these diverse phenotypes, we identified the VGCC α-subunits expressed in the ganglion, investigated aspects of Ca(2+)-dependent neuronal firing patterns, and mapped the intracellular and intercellular distributions of seven VGCC α-subunits in the spiral ganglion in vitro. Initial experiments with qRT-PCR showed that eight of the ten known VGCC α-subunits were expressed in the ganglion and electrophysiological analysis revealed firing patterns that were consistent with the presence of both LVA and HVA Ca(2+) channels. Moreover, we were able to study seven of the α-subunits with immunocytochemistry, and we found that all were present in spiral ganglion neurons, three of which were neuron-specific (Ca(V)1.3, Ca(V)2.2, and Ca(V)3.3). Further characterization of neuron-specific α-subunits showed that Ca(V)1.3 and Ca(V)3.3 were tonotopically-distributed, whereas Ca(V)2.2 was uniformly distributed in apical and basal neurons. Multiple VGCC α-subunits were also immunolocalized to Schwann cells, having distinct intracellular localizations, and, significantly, appearing to distinguish putative compact (Ca(V)2.3, Ca(V)3.1) from loose (Ca(V)1.2) myelin. Electrophysiological evaluation of spiral ganglion neurons in the presence of TEA revealed Ca(2+) plateau potentials with slopes that varied proportionately with the cochlear region from which neurons were isolated. Because afterhyperpolarizations were minimal or absent under these conditions, we hypothesize that differential density and/or kinetics of one or more of the VGCC α-subunits could account for observed tonotopic differences. These experiments have set the stage for defining the clear multiplicity of functional control in neurons and Schwann cells of the spiral ganglion.

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

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

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