L-Type Ca2+ Channel Regulation by Calmodulin and CaBP1

James B Ames

doi:10.3390/biom11121811

Abstract

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.

Highlights

Previous Ca2+ binding data suggest that CaM and Ca2+ binding Protein 1 (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
A structural model of CaBP1 bound to the IQ-motif (Figure 3C) was generated here by homology modeling that was calculated based on the crystal structure of the CaM-IQ complex [44]
The CaBP1 binding to the IQ-motif under basal conditions [35] may serve to block CaM binding to CaV, which may explain how CaBP1 prevents Ca2+ -dependent inactivation (CDI)

Summary

Introduction

Synaptic transmission and neuronal excitability are regulated by the L-type voltagegated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) expressed in the brain and heart [1,2,3,4]. Ca that causes a conformational change in the with the CT1 domain such that the C-lobe of CaM interacts with the ‘‘IQ’’ domain and complex and gives rise to rapid channel inactivation called [29,32,33,34]. Dotted line is the Ca2+ current in the absence of 2+ sensor protein that belongs to the EF-hand is traces a 16.7are kDa. CaBP1, caused by endogenous CaM.

Atomic-level structures of CaM of andCaM

CaBP1 Promotes Activation of Ca

CaM Is Both an Accelerator and a Brake for CaV Channel Activity

Closed

CaBP1 Binding increases to CaV Prevents

Activation by CaBP1