UC Davis

L-type voltage-gated Ca²⁺ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca²⁺ sensor proteins, calmodulin (CaM) and Ca²⁺ binding Protein 1 (CaBP1), that oppositely control Ca²⁺-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca²⁺ levels (caused by CaV channel opening), Ca²⁺-bound CaM binding to CaV is essential for promoting rapid Ca²⁺-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca²⁺-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca²⁺-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca²⁺ binding data suggest that CaM and CaBP1 are both calculated to bind to Ca²⁺ with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca²⁺ concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca²⁺-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca²⁺-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI.