%0 Journal Article
%T Molecular Determinants of Cav1.2 Calcium Channel Inactivation
%A Nikolai M. Soldatov
%J ISRN Molecular Biology
%D 2012
%R 10.5402/2012/691341
%X Voltage-gated L-type Cav1.2 calcium channels couple membrane depolarization to transient increase in cytoplasmic free Ca2+ concentration that initiates a number of essential cellular functions including cardiac and vascular muscle contraction, gene expression, neuronal plasticity, and exocytosis. Inactivation or spontaneous termination of the calcium current through Cav1.2 is a critical step in regulation of these processes. The pathophysiological significance of this process is manifested in hypertension, heart failure, arrhythmia, and a number of other diseases where acceleration of the calcium current decay should present a benefit function. The central issue of this paper is the inactivation of the Cav1.2 calcium channel mediated by multiple determinants. 1. Introduction The voltage-gated inward Ca2+ current ( ) is a common mechanism of transient increase in the cytoplasmic free Ca2+ concentration triggered by cell depolarization. This form of Ca2+ signaling activates essential cellular processes including cardiac contraction [1], regulation of a smooth muscle tone [2], gene expression [3], synaptic plasticity [4] and exocytosis [5]. Complete and rapid termination of Ca2+ influx is mediated by an intricate mechanism of spontaneous calcium channel inactivation, which is crucial for preventing Ca2+ overloading of the cell during action potentials and restoration of the resting sub-¦ÌM cytoplasmic free Ca2+ concentration [6]. This paper will focus on the molecular basis and multiple determinants of the Cav1.2 calcium channel inactivation. 2. Cav1.2: Challenges and Solutions 2.1. Molecular Complexity The Cav1.2 calcium channel is an oligomeric complex composed of the ¦Á1C, ¦Á2¦Ä, and ¦Â subunits [7, 8]. The ion channel pore is formed by the ¦Á1C peptide (Figure 1) that is encoded by the CACNA1C gene. The auxiliary ¦Â and ¦Á2¦Ä subunits are essential for the functional expression and plasma membrane (PM) targeting of the channel [9, 10]. They exist in multiple genomic isoforms generated by four CACNB genes (CACNB1¨C4) and three CACNA2D genes (CACNA2D1¨C3). All three subunits are subject to alternative splicing. Adding to the complexity of the Cav1.2 molecular organization, ¦Â subunits tend to oligomerize [11]. All together, genomic variability, alternative splicing, and hetero-oligomerization generate a plethora of Cav1.2 splice variants that are expressed in cells in species-, tissue-, and developmental-dependent manner, while the change of their fine balance may have significant pathophysiological consequences [12, 13]. Figure 1: Transmembrane topology of the ¦Á 1C
%U http://www.hindawi.com/journals/isrn.molecular.biology/2012/691341/