The voltage-gated ion channels and their structural relatives comprise a superfamily encoded by at least 143 genes in the human genome and are therefore one of the largest superfamilies of signal transduction proteins, following the G protein-coupled receptors and the protein kinases in number [1]. In addition to their prominence in signal transduction, these ion channels are also among the most common drug targets. As for other large protein superfamilies, understanding the molecular relationships among family members, developing a unified, rational nomenclature for the ion channel families and subfamilies, and assigning physiological functions and pharmacological significance to each family member has been an important challenge. Some of the ion channels placed under the 'Voltage-gated' umbrella are not in fact gated by voltage, but for the reasons mentioned above it is useful to consider them within this superfamily. The inwardly rectifying potassium channels, two-pore domain potassium channels (K2P), ryanodine receptors (RyR) and transient receptor potential channels (TRP) are those that are NOT voltage-gated.

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The voltage-dependent anion channels (VDACs) plays a key role in regulating metabolic and energetic flux across the outer mitochondrial membrane. It is involved in the transport of ATP, ADP, pyruvate, malate, and other metabolites, and thus communicates extensively with enzymes from metabolic pathways. They are a class of porin ion channel located on the outer mitochondrial membrane. VDAC1, VDAC2 and VDAC3 are involved in the regulation of apoptosis, cell metabolism, mitochondrial apoptosis, and spermatogenesis [3-4].

The calcium homeostasis modulator (CALHM) ion channels are apparently voltage- and extracellular Ca²⁺-gated, and constitute a novel ion channel family that is widely expressed in the brain and taste buds throughout vertebrates and in sensory neurons and body wall muscles in C. elegans. In humans, the CALHM family encompasses six paralogs, some of which function as non-selective channels that are permeable to large substances such as ATP. CALHM channels are thought to play important roles in neuronal excitability, neurotransmission of tastes, and muscle cell function. The voltage- and extracellular Ca²⁺-dependent gating mechanisms, structural features that define the gate and ion permeation pathway and additional physiological roles, remain to be discovered [2].

1. Catterall WA, Goldin AL, Waxman SG. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev, 57 (4): 397-409. [PMID:16382098]

2. Ma Z, Tanis JE, Taruno A, Foskett JK. (2016) Calcium homeostasis modulator (CALHM) ion channels. Pflugers Arch, 468 (3): 395-403. [PMID:26603282]

3. Magrì A, Reina S, De Pinto V. (2018) VDAC1 as Pharmacological Target in Cancer and Neurodegeneration: Focus on Its Role in Apoptosis. Front Chem, 6: 108. [PMID:29682501]

4. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N. (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med, 31 (3): 227-85. [PMID:20346371]