title: Modified cardiovascular L-type channels in mice lacking the voltage-dependent Ca2+ channel beta3 subunit.
abstract: The beta subunits of voltage-dependent calcium channels are known to modify calcium channel currents through pore-forming alpha1 subunits. Of the four beta subunits reported to date, the beta3 subunit is highly expressed in smooth muscle cells and is thought to consist of L-type calcium channels. To determine the role of the beta3 subunit in the voltage-dependent calcium channels of the cardiovascular system in situ, we performed a series of experiments in beta3-null mice. Western blot analysis indicated a significant reduction in expression of the alpha1 subunit in the plasma membrane of beta3-null mice. Dihydropyridine binding experiments also revealed a significant decrease in the calcium channel population in the aorta. Electrophysiological analyses indicated a 30% reduction in Ca2+ channel current density, a slower inactivation rate, and a decreased dihydropyridine-sensitive current in beta3-null mice. The reductions in the peak current density and inactivation rate were reproduced in vitro by co-expression of the calcium channel subunits in Chinese hamster ovary cells. Despite the reduced channel population, beta3-null mice showed normal blood pressure, whereas a significant reduction in dihydropyridine responsiveness was observed. A high salt diet significantly elevated blood pressure only in the beta3-null mice and resulted in hypertrophic changes in the aortic smooth muscle layer and cardiac enlargement. In conclusion, this study demonstrates the involvement and importance of the beta3 subunit of voltage-dependent calcium channels in the cardiovascular system and in regulating channel populations and channel properties in vascular smooth muscle cells.
authors.affiliation: Department of Pharmacology, Akita University School of Medicine, Akita 010-8543, Japan. manabumurakami@excite.co.jp
authors.forename: Manabu
authors.initials: M
authors.lastname: Murakami
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Myoung-Goo
authors.initials: MG
authors.lastname: Kang
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Murakami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Miyoshi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.forename: Takuzou
authors.initials: T
authors.lastname: Hano
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasai
authors.forename: Shinnsuke
authors.initials: S
authors.lastname: Nakayama
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iijima
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure; D015153:Blotting, Western; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D002319:Cardiovascular System / Q000378:metabolism; D006224:Cricetinae; D004095:Dihydropyridines / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; C038806:1,4-dihydropyridine; D002118:Calcium