title: Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries.
abstract: BACKGROUND
  Physiological functions of mitochondria in contractile arterial myocytes are poorly understood. Mitochondria can uptake calcium (Ca(2+)), but intracellular Ca(2+) signals that regulate mitochondrial Ca(2+) concentration ([Ca(2+)](mito)) and physiological functions of changes in [Ca(2+)](mito) in arterial myocytes are unclear.
  
  
  OBJECTIVE
  To identify Ca(2+) signals that regulate [Ca(2+)](mito), examine the significance of changes in [Ca(2+)](mito), and test the hypothesis that [Ca(2+)](mito) controls functional ion channel transcription in myocytes of resistance-size cerebral arteries.
  
  
  RESULTS
  Endothelin (ET)-1 activated Ca(2+) waves and elevated global Ca(2+) concentration ([Ca(2+)](i)) via inositol 1,4,5-trisphosphate receptor (IP(3)R) activation. IP(3)R-mediated sarcoplasmic reticulum (SR) Ca(2+) release increased [Ca(2+)](mito) and induced mitochondrial depolarization, which stimulated mitochondrial reactive oxygen species (mitoROS) generation that elevated cytosolic ROS. In contrast, a global [Ca(2+)](i) elevation did not alter [Ca(2+)](mito), mitochondrial potential, or mitoROS generation. ET-1 stimulated nuclear translocation of nuclear factor (NF)-kappaB p50 subunit and ET-1-induced IP(3)R-mediated mitoROS elevated NF-kappaB-dependent transcriptional activity. ET-1 elevated voltage-dependent Ca(2+) (Ca(V)1.2) channel expression, leading to an increase in both pressure (myogenic tone)- and depolarization-induced vasoconstriction. Baseline Ca(V)1.2 expression and the ET-1-induced elevation in Ca(V)1.2 expression were both reduced by IP(3)R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF-kappaB subunit knockdown, leading to vasodilation.
  
  
  CONCLUSIONS
  IP(3)R-mediated SR Ca(2+) release elevates [Ca(2+)](mito), which induces mitoROS generation. MitoROS activate NF-kappaB, which stimulates Ca(V)1.2 channel transcription. Thus, mitochondria sense IP(3)R-mediated SR Ca(2+) release to control NF-kappaB-dependent Ca(V)1.2 channel expression in arterial myocytes, thereby modulating arterial contractility.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA.
authors.forename: Damodaran
authors.initials: D
authors.lastname: Narayanan
authors.forename: Qi
authors.initials: Q
authors.lastname: Xi
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002536:Cerebral Arteries / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006706:Homeostasis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014475:Uncoupling Agents / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000975:Antioxidants; C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008164:Luminescent Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D002118:Calcium