title: Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces  short-term synaptic facilitation.
abstract: Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity. Neuronal calcium sensor-1 (NCS-1, frequenin) has been shown to enhance synaptic facilitation, but the underlying mechanism is unclear. We report here that NCS-1 directly interacts with IQ-like motif and calmodulin-binding domain in the C-terminal domain of Ca(V)2.1 channel. NCS-1 reduces Ca2 +-dependent inactivation of P/Q-type Ca2+ current through interaction with the IQ-like motif and calmodulin-binding domain without affecting peak current or activation kinetics. Expression of NCS-1 in presynaptic superior cervical ganglion neurons has no effect on synaptic transmission, eliminating effects of this calcium sensor protein on endogenous N-type Ca2+ currents and the endogenous neurotransmitter release machinery. However, in superior cervical ganglion neurons expressing wild-type Ca(V)2.1 channels, co-expression of NCS-1 induces facilitation of synaptic transmission in response to paired pulses and trains of depolarizing stimuli, and this effect is lost in Ca(V)2.1 channels with mutations in the IQ-like motif and calmodulin-binding domain. These results reveal that NCS-1 directly modulates Ca(V)2.1 channels to induce short-term synaptic facilitation and further demonstrate that CaS proteins are crucial in fine-tuning short-term synaptic plasticity.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Karina
authors.initials: K
authors.lastname: Leal
authors.forename: Venkat G
authors.initials: VG
authors.lastname: Magupalli
authors.forename: Evanthia
authors.initials: E
authors.lastname: Nanou
authors.forename: Gilbert Q
authors.initials: GQ
authors.lastname: Martinez
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D020864:Calcium Channels, N-Type; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins