Calmodulin regulation of voltage-gated calcium channels and beyond

Authored by: Ben-Johny Manu , T. Yue David

Handbook of Ion Channels

Print publication date:  February  2015
Online publication date:  February  2015

Print ISBN: 9781466551404
eBook ISBN: 9781466551428
Adobe ISBN:

10.1201/b18027-40

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Abstract

In recent years, the ubiquitous Ca2+-binding protein calmodulin (CaM) has emerged as a preeminent modulator of ion channel function (Saimi and Kung 2002), exhibiting exquisite Ca2+-sensing capabilities (Chin and Means 2000; Tadross et al. 2008) and supporting vital Ca2+ feedback to many biological systems. An early example of such modulation was discovered via mutations in CaM that resulted in aberrant motile behavior of Paramecium. Organisms were either underexcitable or overexcitable to certain stimuli, reflecting the loss of a Ca2+-dependent Na+ current or K+ current respectively (Kink et al. 1990). More recently, numerous ion channels have been found to be regulated by CaM, as reviewed elsewhere (Budde et al. 2002; Saimi and Kung 2002; Trudeau and Zagotta 2003; Halling et al. 2006; Gordon-Shaag et al. 2008; Minor and Findeisen 2010; Adelman et al. 2012; Van Petegem et al. 2012). This review will mainly focus on voltage-gated Ca2+ channels, but we briefly review the ion channel field in general, as follows. In small-conductance K+ channels (SK channels), CaM initially preassociates in a Ca2+-independent manner (Xia et al. 1998; Schumacher et al. 2004) and then activates these channels in response to submicromolar elevations in cytosolic Ca2+ (Xia et al. 1998), generating after hyperpolarizing current that shapes neuronal excitability (Stocker 2004; Adelman et al. 2012). The The KCNQ (Kv7) channels also constitutively bind Ca2+-free CaM (apoCaM) (Ghosh et al. 2006), but intracellular Ca2+ may either inhibit (Gamper and Shapiro 2003; Gamper et al. 2005) or enhance these K+ currents in an isoform specific manner (Ghosh et al. 2006; Shamgar et al. 2006). The cyclic nucleotide–gated (CNG) ion channels are also bestowed with apoCaM (Bradley et al. 2005), that upon Ca2+ binding induce a conformational change (Trudeau and Zagotta 2004) that inactivates channel activity (Bradley et al. 2004; Chen and Yau 1994; Trudeau and Zagotta 2003; Bradley et al. 2005). N-methyl-D-aspartate (NMDA) glutamate receptor activity is also downregulated by the direct interaction of Ca2+/CaM with the carboxy terminus of the channel (Ehlers et al. 1996; Zhang et al. 1998). Ca2+/CaM has been shown to bind a number of Transient Receptor Potential (TRP) channels, though the functional consequences of such binding remain controversial (Gordon-Shaag et al. 2008; Lau et al. 2012; Numazaki et al. 2003; Rosenbaum et al. 2004; Mercado et al. 2010). The Ca2+ release-activated Ca2+ channels (CRACs) undergo Ca2+-dependent inactivation (CDI) orchestrated by CaM binding to Stromal interaction molecules (STIM) (Mullins et al. 2009). molecules (Mullins et al. 2009). Lastly, both the voltage-gated Na (Deschenes et al. 2002; Tan et al. 2002; Van Petegem et al. 2012; Ben-Johny et al. 2014; Biswas et al. 2008; Sarhan et al. 2009) and Ca2+ channels (Lee et al. 1999; Peterson et al. 1999; Zuhlke et al. 1999; DeMaria et al. 2001; Budde et al. 2002; Halling et al. 2006; Minor and Findeisen 2010) are under tight feedback regulation by Ca2+/CaM, with far-reaching biological consequences (Alseikhan et al. 2002; Xu and Wu 2005; Adams et al. 2010). This review focuses on the rapid millisecond modulation of gating of voltage-gated Ca2+ channels, rich with biological impact, therapeutic possibilities, and mechanistic elegance.

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