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-μM 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 α1C, α2δ, and β subunits [7, 8]. The ion channel pore is formed by the α1C peptide (Figure 1) that is encoded by the CACNA1C gene. The auxiliary β and α2δ 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 (CACNB1–4) and three CACNA2D genes (CACNA2D1–3). All three subunits are subject to alternative splicing. Adding to the complexity of the Cav1.2 molecular organization, β 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 α 1C
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