Calmodulin Interactions withCa_v1 andCa_v2 Voltage‐Gated Calcium ChannelIQDomains

Abstract

High‐voltage‐activated calcium channels (Ca V 1s and Ca V 2s) are transmembrane protein complexes that couple membrane depolarization to cellular calcium entry. Because calcium is an intracellular messenger and Ca V s are important calcium sources, Ca V s have a key role in the conversion of electrical signals into the chemical signaling cascades that drive a variety of vital physiological processes in nerve and muscle. These include excitation‐contraction coupling, hormone release, gene regulation, and synaptic transmission. Ca V s are regulated by a diverse set of feedback mechanisms. Two important forms of activity‐dependent feedback modulation involve interactions between calcium‐calmodulin (Ca 2+ /CaM) and the Ca V α 1 pore‐forming subunit of Ca V 1s and Ca V 2s: calcium‐dependent inactivation (CDI) in which calcium influx promotes channel closing following activation, and calcium‐dependent facilitation (CDF), a process that enhances channel opening in response to elevated cytoplasmic calcium. The main site of action for Ca 2+ /CaM is a motif, known as an IQ domain , located on the C‐terminal cytoplasmic tail of the Ca V α 1 pore‐forming subunit. Strikingly, different Ca 2+ /CaM lobes are responsible for CDI and CDF in Ca V 1 and Ca V 2 channels. Crystallographic studies have indicated a structural basis for the apparent inversion of lobe‐specific roles in CDI and CDF in which Ca 2+ /CaM binds Ca V 1 and Ca V 2 IQ domains in opposite orientations.

A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation

“…This process contributes to autism (Limpitikul et al, 2016), vision (Singh et al, 2006), and cardiac action potential duration (Alseikhan et al, 2002;Dick et al, 2016;Mahajan et al, 2008;Morotti et al, 2012;Splawski et al, 2004Splawski et al, , 2005 and is impacted by alternative splicing (Bartels et al, 2018;Shen et al, 2006;Tan et al, 2011), RNA editing (Huang et al, 2012), as well as mutations in CaM associated with long QT syndrome (Limpitikul et al, 2014(Limpitikul et al, , 2017. Because CDI is central to both the biophysical and physiological functions of Ca V s, its molecular origins have been extensively investigated, especially from the vantage point of the intracellular, CaM-based sensor and the role of the IQ domain (Ben-Johny and Yue, 2014;Minor and Findeisen, 2010;Kim et al, 2008Kim et al, , 2010Mori et al, 2008;Van Petegem et al, 2005). Although the involvement of this CaM-based sensor in CDI is firmly established, how conformational changes of this cytoplasmic element result in the cessation of ion flow through the channel and the exact CDI endpoint have remained unresolved (Babich et al, 2007;Barrett and Tsien, 2008;Cens et al, 2006;Findeisen and Minor, 2009;Kim et al, 2004;.…”

“…Three Ca V channel intracellular elements contribute to CDI: the N-terminal cytoplasmic domain (Ben Johny et al, 2013;Dick et al, 2008;Ivanina et al, 2000;Tadross et al, 2008), the Ca V b/I-II loop complex (Almagor et al, 2012;Findeisen and Minor, 2009), and the C-terminal tail:CaM complex (Ben-Johny and Minor and Findeisen, 2010;Kim et al, 2008Kim et al, , 2010Lee et al, 1999;Mori et al, 2008;Peterson et al, 1999;Van Petegem et al, 2005;Z€ uhlke et al, 1999), with the C-terminal tail:CaM complex serving as the Ca 2+ sensor that initiates CDI. Given this functionally interconnected network of domains that influence CDI, there has been an ongoing search to identify the molecular endpoints of Ca V CDI (Barrett and Tsien, 2008;Benmocha Guggenheimer et al, 2016;.…”

“…Ca V a 1 shares the overall architecture found throughout the voltage-gated ion channel (VGIC) superfamily but requires auxiliary subunits for proper function (Campiglio and Flucher, 2015;Dolphin, 2016). Complexes with two intracellular components that bind to the cytosolic I-II loop and C-terminal tail, the Ca V b subunit (Chen et al, 2004;Opatowsky et al, 2004;Van Petegem et al, 2004) and calmodulin (CaM) (Fallon et al, 2009;Kim et al, 2008Kim et al, , 2010Mori et al, 2008;Van Petegem et al, 2005), respectively, are particularly important for activity-dependent feedback modulation by the two principal Ca V inactivation mechanisms, voltage-dependent inactivation (VDI) (Cens et al, 2006;Stotz et al, 2004) and CDI (Ben-Johny and Cens et al, 2006;Christel and Lee, 2011;Halling et al, 2006).…”

“…The molecular origins of CDI have been extensively investigated, especially from the vantage point of the intracellular, CaM-based sensor apparatus and the role of the CaM-binding IQ domain (Ben-Johny and Yue, 2014;Fallon et al, 2005;Minor and Findeisen, 2010;Kim et al, 2008Kim et al, , 2010Mori et al, 2008;Van Petegem et al, 2005). Although the involvement of this CaMbased sensor in CDI is clear (Ben-Johny and Yue, 2014;Minor and Findeisen, 2010;Kim et al, 2008Kim et al, , 2010Lee et al, 1999;Mori et al, 2008;Peterson et al, 1999;Van Petegem et al, 2005;Z€ uhlke et al, 1999) (A) Sequence alignment of pore helices and selectivity filters of Na V Ae1 (Shaya et al, 2014), calcium-selective BacNa V s Ca V Bh1 (Yue et al, 2002), Ca V Sp1p (Shaya et al, 2011), and human Ca V 1 and Ca V 2 exemplars: Ca V 1.1 (UniProtKB: Q13698), Ca V 1.2 (UniProtKB: Q13936), Ca V 1.3 (UniProtKB: Q01668), and Ca V 2.1 (UniProtKB: O00555). SF sites (0) and (+1) are highlighted in orange and red, respectively.…”

The Role of Physical Stimuli on Calcium Channels in Chondrogenic Differentiation of Mesenchymal Stem Cells

“…α2δ, β, and γ subunits modulate the functional properties of VOCCs. Calmodulin (CaM) is a ubiquitous calcium binding protein bound to the I-II loop of the CaVs and is also a part of VOCCs, involved in a further Ca 2+ signaling [ 18 ] ( Figure 2 ).…”