title: Calcium controls smooth muscle TRPC gene transcription via the CaMK/calcineurin-dependent pathways.
abstract: Transient receptor potential protein family C (TRPC) has been proposed as a candidate for channels involved in capacitative Ca(2+) entry (CCE) mechanisms, but the modulation of their gene expression remains unexplored. In this study we show that guinea pig gallbladder smooth muscle contains mRNA encoding TRPC1, TRPC2, TRPC3, and TRPC4 proteins whose abundance depends on cytosolic Ca(2+) level ([Ca(2+)](i)). Thus lowering the levels of cellular calcium with the chelators EGTA and BAPTA AM results in a downregulation of TRPC1-TRPC4 gene and protein expression. In contrast, activation of Ca(2+) influx through L-type Ca(2+) channels and Ca(2+) release from intracellular stores induced an increase in TRPC1-TRPC4 mRNA and protein abundance. Activation of Ca(2+)/calmodulin-dependent kinases (CaMK) and phosphorylation of cAMP-response element binding protein accounts for the increase in TRPC mRNA transcription in response to L-type channel-mediated Ca(2+) influx . In addition to this mechanism, activation of TRPC gene expression by intracellular Ca(2+) release also involves calcineurin pathway. According to the proposed role for these channels, activation of CCE induced an increase in TRPC1 and TRPC3 mRNA abundance, which depends on the integrity of the calcineurin and CaMK pathways. These findings show for the first time an essential autoregulatory role of Ca(2+) in Ca(2+) homeostasis at the level of TRPC gene and protein expression.
authors.affiliation: Department of Physiology, Nursing School, University of Extremadura, Avenida Universidad s/n, 10071 Cáceres, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Morales
authors.forename: Amalia
authors.initials: A
authors.lastname: Diez
authors.forename: Antonio
authors.initials: A
authors.lastname: Puyet
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Camello
authors.forename: Cristina
authors.initials: C
authors.lastname: Camello-Almaraz
authors.forename: Jose M
authors.initials: JM
authors.lastname: Bautista
authors.forename: María J
authors.initials: MJ
authors.lastname: Pozo
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D005704:Gallbladder / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium