Physiology, Pathophysiology and Pharmacology of Calcium Channels

Dear Colleagues,

Calcium ions (Ca²⁺) affect nearly all aspects of cellular function. Thus, Ca²⁺ is a universal intracellular messenger that participates in numerous biological processes, including muscle contraction, excitation conduction, gene expression, cell growth, and cell death. This incredible versatility necessitates the tight regulation of intracellular Ca²⁺ concentration ([Ca²⁺]_i) to ensure coordination among the multiple processes involving Ca²⁺ that underlie normal cell functioning. Underlying the physiological function and effectiveness of Ca²⁺ is the 20,000-fold gradient maintained by cells between their intracellular (∼100 nM free) and extracellular (mM) concentrations. Disrupted regulation of [Ca²⁺]_i often leads to cell dysfunction, such as occurs in life-threatening diseases. Ca²⁺ influx across the plasma membrane occurs in multiple ways, including a phase of Ca²⁺ influx via calcium channels. The role of voltage-gated Ca²⁺ channels has long been extensively studied in physiological and pathophysiological conditions. Furthermore, both molecular genetic and pharmacological approaches have revealed the existence of functional Ca²⁺ channels in a variety of excitable and non-excitable cells. In this context, Ca²⁺ entry has long been recognized to be important to the function of excitable cells and the subsequent discovery of voltage-activated calcium conductances in these cells. Historically, these observations were rapidly followed by the identification of multiple subtypes of calcium conductance in different tissues. These were initially termed low- and high-voltage activated currents, but were then further subdivided into L-, N-, P/Q-, R-, and T-type calcium currents on the basis of pharmacology, voltage-dependent and kinetic properties, and single channel conductance. Purification of the Ca²⁺ channel allowed for the molecular identification of the pore-forming a and auxiliary α2/δ, β, and ϒ subunits present in these calcium channel complexes. These advances then led to the cloning of the different subunits, which permitted molecular characterization, to match the cloned channels with a physiological function. Studies with knockout/overexpression in mutant mice then allowed for further investigation of physiological and pathophysiological roles of these channels. In terms of clinical pharmacology, L-type channels are targets for the widely used antihypertensive 1,4-dihydropyridines and other calcium channel blockers, N-type channels are a drug target in pain, and α2/δ is the therapeutic target of the drugs used in neuropathic pain and as anticonvulsants. Recent studies have allowed for a deeper understanding of Ca²⁺ permeation through the channel pore and the structure of both the pore-forming and auxiliary subunits. Voltage-gated calcium channels are subject to multiple pathways of modulation by G-protein and second messenger regulation. Furthermore, their trafficking pathways, subcellular localization, and functional specificity are the subjects of active investigation. Furthermore, investigation of transcriptional, post-transcriptional, and translational modulation of Ca²⁺ channels has revealed multiple modulatory signals of Ca²⁺ channels in a wide variety of cells. This Special Issue focuses on recent research that elucidates cellular and molecular mechanisms for Ca²⁺ channel regulation and suggests new implications for calcium channel function and dysfunction in excitable and non-excitable cells, possibly related to ion-channel-mediated diseases or pathophysiology.

Prof. Dr. Katsushige Ono
Guest Editor

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• calcium channels
• calcium homeostasis
• calcium signaling
• calcium-dependent remodeling of cells
• membrane potentials
• intracellular calcium