Modulation of Ca 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 2.1 pore-forming α subunit to optimize neurotransmitter release from presynaptic terminals by allowing secretory vesicles docking near the Ca entry pathway， and by modulating the voltage dependence of channel steady-state inactivation. Ca influx through Ca 2.1 also promotes channel inactivation. This process seems to involve Ca -calmodulin interaction with two adjacent sites in the α carboxyl tail (C-tail) (the IQ-like motif and the Calmodulin-Binding Domain (CBD) site)， and contributes to long-t... More
Modulation of Ca 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 2.1 pore-forming α subunit to optimize neurotransmitter release from presynaptic terminals by allowing secretory vesicles docking near the Ca entry pathway， and by modulating the voltage dependence of channel steady-state inactivation. Ca influx through Ca 2.1 also promotes channel inactivation. This process seems to involve Ca -calmodulin interaction with two adjacent sites in the α 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 determines the degree of channel inactivation by both voltage and Ca . Here， we explore the cross talk between β subunits， Ca ， and syntaxin-1A-modulated Ca 2.1 inactivation， highlighting the α domains involved in such process. β -containing Ca 2.1 channels show syntaxin-1A-modulated but no Ca -dependent steady-state inactivation. Conversely， β -containing Ca 2.1 channels show Ca -dependent but not syntaxin-1A-modulated steady-state inactivation. A LI-II deletion confers Ca -dependent inactivation and prevents modulation by syntaxin-1A in β -containing Ca 2.1 channels. Mutation of the IQ-like motif， unlike CBD deletion， abolishes Ca -dependent inactivation and confers modulation by syntaxin-1A in β -containing Ca 2.1 channels. Altogether， these results suggest that LI-II structural modifications determine the regulation of Ca 2.1 steady-state inactivation either by Ca or by SNAREs but not by both.
