Calcium Channel Diversity

Abstract

Voltage‐gated calcium channels (VGCCs) open as a result of plasma membrane depolarisation. When open, they allow Ca2+ ions to pass down their electrochemical gradient. Different VGCCs can be distinguished both physiologically and pharmacologically in native tissues. There are ten mammalian genes encoding Ca2+ channel α1 subunits, and these map well on to the endogenous channels identified by electrophysiological studies. The subunit composition of the channel complexes, and the role of the auxiliary subunits, is also discussed. Information from structure–function studies and from structural biology is able to provide insight into the mechanism of action of these channels, for example regarding gating and ion selectivity. The different channels have widely divergent tissue distributions and their distinctive individual properties allow them to fulfil many and varied functions. There are also several forms of second messenger‐mediated modulation of the different channels, including regulation by G proteins and by Ca2+‐calmodulin.

Key Concepts

  • VGCCs, when open, allow Ca2+ ions to pass down their electrochemical gradient.
  • Opening of VGCCs occurs in response to membrane depolarisation sensed by the S4 voltage sensors.
  • The exquisite selectivity of VGCCs for Ca2+ is a result of the presence of four glutamate (or aspartate) residues in the selectivity filter of the pore, whose side chains coordinate Ca2+.
  • VGCCs are usually complexes of multiple subunits: α1, which comprises the channel itself, associated with auxiliary subunits, α2δ and β. A γ subunit is also present in the skeletal muscle channel complex.
  • There are ten mammalian VGCC α1 subunits: four CaV1 channels are termed L‐type, three CaV2 channels are termed P/Q, N, and R; and three CaV3 channels are termed T‐type.
  • The α2δ and β auxiliary subunits increase channel trafficking and affect CaV1 and CaV2 channel properties.
  • The CaV3 T‐type channels do not associate with auxiliary subunits.
  • Inhibitory modulation of CaV2 channels by G‐protein coupled receptors is mediated by Gβγ subunits which act in a voltage‐dependent manner.

Keywords: calcium channel; Ca2+ ions; permeation; gating; neuron; excitable cell; neuron; heart; modulation

Figure 1. High and low voltage activated calcium channel currents in dorsal root ganglion neurons. (a) Current voltage (IV) plot recorded from a neuron possessing both LVA and HVA current components. The recording was performed in the presence of tetrodotoxin (1 μM) and nifedipine (1 μM), and 1 mM Ba2+ was the charge carrier. (b) Example calcium channel currents from a neuron possessing both LVA (test potential −10 mV) and HVA (test potential +5 mV) components. Holding potential (HP) −80 mV.
Figure 2. Calcium channel organisation. (a) Cloned calcium channel homology and nomenclature for CACNA1 genes (black), CaV protein classification (red), original name for cloned α1 subunits (blue) and the name derived from physiological and pharmacological experiments (green). (b) The topology of the calcium channel complex. The α1 subunit, shows the four homologous domains each with 6 transmembrane segments, an S4 voltage sensor (green), containing a motif of positively charged amino acid residues, and the P‐loop between S5 and S6, which comprise the pore domain (red). The α2δ and β subunit domains are also shown.
Figure 3. Structure of Calcium channel complex. Overall structure of the rabbit CaV1.1 complex, as updated from Wu et al. (). The α1 (green), α2δ‐1 (salmon pink), β1a (SH3 domain in cyan and GK domain in magenta) and γ1 subunits (yellow) are shown, with Ca2+ in red (enlarged for visibility). Parts of the intracellular sequences are unresolved. Prepared using Pymol from PDB ID: 5GJV.
Figure 4. CaV2.2 single‐channel and whole‐cell currents. (a) Examples of expressed CaV2.2 single‐channel and ensemble average currents. The cDNA for the calcium channel subunits (including an α2δ and β subunit) was transfected into a cell line which contains no endogenous calcium channels. In this way its properties may be investigated in isolation. (b) Example of an ensemble average current obtained by summation of multiple single‐channel current traces recorded in cell‐attached patch mode. The experiment was performed as described previously (Meir et al., ). (c) Example of whole‐cell current IV plot for CaV2.2, HP – 60 mV. (d) Example of currents making up the IV plot in (c); HP – 60 mV, test potentials to −10, 0, +10, +20, +30 mV.
Figure 5. Idealised neuron with the most prevalent distribution of VGCCs. Different neuronal cell types have widely varying complements of VGCCs, for example they may not express T‐type currents. The bold letters indicate the predominant distributions of the different VGCC subtypes when they are present.
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Further Reading

Dolphin AC (2016) Voltage‐gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. The Journal of Physiology 594: 5369–5390.

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Zamponi GW, Striessnig J, Koschak A and Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage‐gated calcium channels and their future therapeutic potential. Pharmacological Reviews 67: 821–870.

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Dolphin, Annette C(Nov 2019) Calcium Channel Diversity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000087.pub3]