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

• Published in: Physiological reports 2018-01, Vol.6 (2)
• Main Authors: Serra, Selma Angèlica, Gené, Gemma G, Xabier Elorza‐Vidal, José M. Fernández‐Fernández
• Format: Article
• Language: English
• Subjects: Calcium (intracellular); Calcium channels; Calcium channels (voltage-gated); Calcium influx; Calcium signalling; Calcium-binding protein; Calmodulin; Channel gating; Gene deletion; Intracellular; Intracellular signalling; Neurotransmitter release; Physiology; Potentiation; Secretory vesicles; Spatial discrimination learning; Spatial memory; Synaptic plasticity; Syntaxin
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13557

Modulation of CaV2.1 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 CaV2.1 pore‐forming α1A subunit to optimize neurotransmitter release from presynaptic terminals by allowing secretory vesicles docking near the Ca2+ entry pathway, and by modulating the voltage dependence of channel steady‐state inactivation. Ca2+ influx through CaV2.1 also promotes channel inactivation. This process seems to involve Ca2+‐calmodulin interaction with two adjacent sites in the α1A 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 α1A determines the degree of channel inactivation by both voltage and Ca2+. Here, we explore the cross talk between β subunits, Ca2+, and syntaxin‐1A‐modulated CaV2.1 inactivation, highlighting the α1A domains involved in such process. β3‐containing CaV2.1 channels show syntaxin‐1A‐modulated but no Ca2+‐dependent steady‐state inactivation. Conversely, β2a‐containing CaV2.1 channels show Ca2+‐dependent but not syntaxin‐1A‐modulated steady‐state inactivation. A LI‐II deletion confers Ca2+‐dependent inactivation and prevents modulation by syntaxin‐1A in β3‐containing CaV2.1 channels. Mutation of the IQ‐like motif, unlike CBD deletion, abolishes Ca2+‐dependent inactivation and confers modulation by syntaxin‐1A in β2a‐containing CaV2.1 channels. Altogether, these results suggest that LI‐II structural modifications determine the regulation of CaV2.1 steady‐state inactivation either by Ca2+ or by SNAREs but not by both.