Ca(2+) channel alpha(1B) subunit (Ca(V) 2.2) knockout mouse reveals a predominant role of N-type channels in the sympathetic regulation of the circulatory system.
N-type voltage-dependent Ca(2+) channels (VDCCs), predominantly localized in the nervous system, have been proposed to play vital roles in a variety of neuronal functions such as neurotransmitter release at sympathetic nerve terminals. To directly approach the elucidation of the physiological significance of N-type VDCCs in the autonomic nervous system, alpha(1B) subunit (Ca(V) 2.2)-deficient mice were generated, in which peripheral neurons showed a complete and selective elimination of N-type channel currents sensitive to omega-conotoxin GVIA (the peptide toxin from the fish-hunting cone snail Conus geographus), without a significant effect on the activity of other VDCC types. In isolated left atria prepared from N-type-deficient mice, the positive inotropic response mediated by the sympathetic nervous system was dramatically decreased, whereas the negative inotropic response mediated by parasympathetic neurons was nearly intact compared with those of normal mice. The baroreflex response to bilateral carotid occlusion was markedly reduced in the mutant mice. Interestingly, the mutant mice showed sustained elevation of heart rate and blood pressure. These results provide direct in vivo evidence for an essential role of N-type VDCCs in maintaining the normal function of the sympathetic nervous system in circulatory regulation, demonstrating a potential of N-type VDCC-deficient mice as a useful model for studying disorders attributable to sympathetic nerve dysfunction.
Mori
Yasuo
Y
Division of Molecular and Cellular Physiology, Center for Integrative Bioscience, Okazaki National Research Intitutes and School of Life Sciences, the Graduate University of Advanced Studies, Okazaki, Aichi, Japan. moriy@nips.ac.jp
Nishida
Motohiro
M
Shimizu
Shunichi
S
Ishii
Masakazu
M
Yoshinaga
Takashi
T
Ino
Mitsuhiro
M
Sawada
Kohei
K
Niidome
Tetsuhiro
T
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D002320:Cardiovascular Physiological Phenomena; D051379:Mice; D018345:Mice, Knockout; D013564:Sympathetic Nervous System / Q000502:physiology*
D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type