title: Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II.
abstract: The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) is activated by vasoconstrictors in vascular smooth muscle cells (VSMC), but its impact on vasoconstriction remains unknown. We hypothesized that CaMKII inhibition in VSMC decreases vasoconstriction. Using novel transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), we investigated the effect of CaMKII inhibition on L-type Ca(2+) channel current (ICa), cytoplasmic and sarcoplasmic reticulum Ca(2+), and vasoconstriction in mesenteric arteries. In mesenteric VSMC, CaMKII inhibition significantly reduced action potential duration and the residual ICa 50 ms after peak amplitude, indicative of loss of L-type Ca(2+) channel-dependent ICa facilitation. Treatment with angiotensin II or phenylephrine increased the intracellular Ca(2+) concentration in wild-type but not TG SM-CaMKIIN VSMC. The difference in intracellular Ca(2+) concentration was abolished by pretreatment with nifedipine, an L-type Ca(2+) channel antagonist. In TG SM-CaMKIIN VSMC, the total sarcoplasmic reticulum Ca(2+) content was reduced as a result of diminished sarcoplasmic reticulum Ca(2+) ATPase activity via impaired derepression of the sarcoplasmic reticulum Ca(2+) ATPase inhibitor phospholamban. Despite the differences in intracellular Ca(2+) concentration, CaMKII inhibition did not alter myogenic tone or vasoconstriction of mesenteric arteries in response to KCl, angiotensin II, and phenylephrine. However, it increased myosin light chain kinase activity. These data suggest that CaMKII activity maintains intracellular calcium homeostasis but is not required for vasoconstriction of mesenteric arteries.
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Prasad
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nuno
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Fred Y
authors.initials: FY
authors.lastname: Shen
authors.forename: Mei-ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Lamping
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000099211:Phospholamban; D000096926:Benzenesulfonamides
chemical_list: D000804:Angiotensin II; D001596:Benzylamines; D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009219:Myosin-Light-Chain Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013449:Sulfonamides; D000099211:Phospholamban; C072105:KN 93; D000096926:Benzenesulfonamides; C506947:Atp2a2 protein, mouse
keywords: Ca2+/calmodulin-dependent protein kinase type 2; L-type Ca2+ channel; calcium signaling; myometrial contraction