Cross talk between β subunits, intracellular Ca(2+) signaling, and SNAREs in the modulation of Ca(V)2.1 channel steady‐state inactivation

Modulation of Ca(V)2.1 channel activity plays a key role in interneuronal communication and synaptic plasticity. SNAREs interact with a specific synprint site at the second intracellular loop (LII‐III) of the Ca(V)2.1 pore‐forming α (1A) subunit to optimize neurotransmitter release from presynaptic terminals by allowing secretory vesicles docking near the Ca(2+) entry pathway, and by modulating the voltage dependence of channel steady‐state inactivation. Ca(2+) influx through Ca(V)2.1 also promotes channel inactivation. This process seems to involve Ca(2+)‐calmodulin interaction with two adjacent sites in the α (1A) carboxyl tail (C‐tail) (the IQ‐like motif and the Calmodulin‐Binding Domain (CBD) site), and contributes to long‐term potentiation and spatial learning and memory. Besides, binding of regulatory β subunits to the α interaction domain (AID) at the first intracellular loop (LI‐II) of α (1A) determines the degree of channel inactivation by both voltage and Ca(2+). Here, we explore the cross talk between β subunits, Ca(2+), and syntaxin‐1A‐modulated Ca(V)2.1 inactivation, highlighting the α (1A) domains involved in such process. β (3)‐containing Ca(V)2.1 channels show syntaxin‐1A‐modulated but no Ca(2+)‐dependent steady‐state inactivation. Conversely, β (2a)‐containing Ca(V)2.1 channels show Ca(2+)‐dependent but not syntaxin‐1A‐modulated steady‐state inactivation. A LI‐II deletion confers Ca(2+)‐dependent inactivation and prevents modulation by syntaxin‐1A in β (3)‐containing Ca(V)2.1 channels. Mutation of the IQ‐like motif, unlike CBD deletion, abolishes Ca(2+)‐dependent inactivation and confers modulation by syntaxin‐1A in β (2a)‐containing Ca(V)2.1 channels. Altogether, these results suggest that LI‐II structural modifications determine the regulation of Ca(V)2.1 steady‐state inactivation either by Ca(2+) or by SNAREs but not by both.