title: Metabotropic regulation of RhoA/Rho-associated kinase by L-type Ca2+ channels: new mechanism for depolarization-evoked mammalian arterial contraction.
abstract: BACKGROUND
  Sustained vascular smooth muscle contraction is mediated by extracellular Ca(2+) influx through L-type voltage-gated Ca(2+) channels (VGCC) and RhoA/Rho-associated kinase (ROCK)-dependent Ca(2+) sensitization of the contractile machinery. VGCC activation can also trigger an ion-independent metabotropic pathway that involves G-protein/phospholipase C activation, inositol 1,4,5-trisphosphate synthesis, and Ca(2+) release from the sarcoplasmic reticulum (calcium channel-induced Ca(2+) release). We have studied the functional role of calcium channel-induced Ca(2+) release and the inter-relations between Ca(2+) channel and RhoA/ROCK activation.
  
  
  RESULTS
  We have used normal and genetically modified animals to study single myocyte electrophysiology and fluorimetry as well as cytosolic Ca(2+) and diameter in intact arteries. These analyses were complemented with measurement of tension and RhoA activity in normal and reversibly permeabilized arterial rings. We have found that, unexpectedly, L-type Ca(2+) channel activation and subsequent metabotropic Ca(2+) release from sarcoplasmic reticulum participate in depolarization-evoked RhoA/ROCK activity and sustained arterial contraction. We show that these phenomena do not depend on the change in the membrane potential itself, or the mere release of Ca(2+) from the sarcoplasmic reticulum, but they require the simultaneous activation of VGCC and the downstream metabotropic pathway with concomitant Ca(2+) release. During protracted depolarizations, refilling of the stores by a residual extracellular Ca(2+) influx through VGCC helps maintaining RhoA activity and sustained arterial contraction.
  
  
  CONCLUSIONS
  These findings reveal that calcium channel-induced Ca(2+) release has a major role in tonic vascular smooth muscle contractility because it links membrane depolarization and Ca(2+) channel activation with metabotropic Ca(2+) release and sensitization (RhoA/ROCK stimulation).
authors.affiliation: Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Tenorio
authors.forename: Cristina
authors.initials: C
authors.lastname: Porras-González
authors.forename: Antonio
authors.initials: A
authors.lastname: Castellano
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Valle-Rodríguez
authors.forename: José
authors.initials: J
authors.lastname: López-Barneo
authors.forename: Juan
authors.initials: J
authors.lastname: Ureña
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D003329:Coronary Vasospasm / Q000503:physiopathology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D020301:Vasospasm, Intracranial / Q000503:physiopathology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: C514350:CACNA1C protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D007211:Indoles; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D009543:Nifedipine; D002118:Calcium; C000543:cyclopiazonic acid