title: The voltage-dependent L-type Ca2+ (CaV1.2) channel C-terminus fragment is a bi-modal vasodilator.
abstract: Voltage-dependent L-type Ca(2+) channels (CaV1.2) are the primary Ca(2+) entry pathway in vascular smooth muscle cells (myocytes). CaV1.2 channels control systemic blood pressure and organ blood flow and are pathologically altered in vascular diseases, which modifies vessel contractility. The CaV1.2 distal C-terminus is susceptible to proteolytic cleavage, which yields a truncated CaV1.2 subunit and a cleaved C-terminal fragment (CCt). Previous studies in cardiac myocytes and neurons have identified CCt as both a transcription factor and CaV1.2 channel inhibitor, with different signalling mechanisms proposed to underlie some of these effects. CCt existence and physiological functions in arterial myocytes are unclear, but important to study given the functional significance of CaV1.2 channels. Here, we show that CCt exists in myocytes of both rat and human resistance-size cerebral arteries, where it locates to both the nucleus and plasma membrane. Recombinant CCt expression in arterial myocytes inhibited CaV1.2 transcription and reduced CaV1.2 protein. CCt induced a depolarizing shift in the voltage dependence of both CaV1.2 current activation and inactivation, and reduced non-inactivating current in myocytes. Recombinant truncated CCt lacking a putative nuclear localization sequence (92CCt) did not locate to the nucleus and had no effect on arterial CaV1.2 transcription or protein. However, 92CCt shifted the voltage dependence of CaV1.2 activation and inactivation similarly to CCt. CCt and 92CCt both inhibited pressure- and depolarization-induced vasoconstriction, although CCt was a far more effective vasodilator. These data demonstrate that endogenous CCt exists and reduces both CaV1.2 channel expression and voltage sensitivity in arterial myocytes. Thus, CCt is a bi-modal vasodilator.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Centre, 894 Union Avenue, Suite 426, Memphis, TN 38163, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Bannister
authors.forename: Marie Dennis
authors.initials: MD
authors.lastname: Leo
authors.forename: Damodaran
authors.initials: D
authors.lastname: Narayanan
authors.forename: Wanchana
authors.initials: W
authors.lastname: Jangsangthong
authors.forename: Anitha
authors.initials: A
authors.lastname: Nair
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Evanson
authors.forename: Judith
authors.initials: J
authors.lastname: Pachuau
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Gabrick
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Boop
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
mesh_terms: D000200:Action Potentials; D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002536:Cerebral Arteries / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D019913:Nuclear Localization Signals; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014664:Vasodilation
chemical_list: C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D019913:Nuclear Localization Signals