Ca2+-dependent modulation of voltage-gated Ca2+ channels

Background: Voltage-gated (Ca-v) Ca2+ channels are multi-subunit complexes that play diverse roles in a wide variety of tissues. A fundamental mechanism controlling Ca-v channel function involves the Ca2+ ions that permeate the channel pore. Ca2+ influx through Ca-v channels mediates feedback regulation to the channel that is both negative (Ca2+-dependent inactivation, CDI) and positive (Ca2+-dependent facilitation, CDF). Scope of review: This review highlights general mechanisms of CDI and CDF with an emphasis on how these processes have been studied electrophysiologically in native and heterologous expression systems. Major conclusions: Electrophysiological analyses have led to detailed insights into the mechanisms and prevalence of CDI and CDF as Ca-v channel regulatory mechanisms. All Ca-v channel family members undergo some form of Ca2+-dependent feedback that relies on CaM or a related Ca2+ binding protein. Tremendous progress has been made in characterizing the role of CaM in CDI and CDF. Yet, what contributes to the heterogeneity of CDI/CDF in various cell-types and how Ca2+-dependent regulation of Ca-v channels controls Ca2+ signaling remain largely unexplored. General significance: Ca2+ influx through Ca-v channels regulates diverse physiological events including excitation-contraction coupling in muscle, neurotransmitter and hormone release, and Ca2+-dependent gene transcription. Therefore, the mechanisms that regulate channels, such as CDI and CDF, can have a large impact on the signaling potential of excitable cells in various physiological contexts. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling. (C) 2012 Elsevier B.V. All rights reserved.