Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.
N-type voltage-dependent calcium channels (VDCCs) play determining roles in calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-overexpressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as electrocardiography, blood pressure, echocardiography, and isovolumic contraction of the left ventricle with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel-specific blockers in electrocardiography, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal calcium channel currents, indicating unchanged calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.
Murakami
Manabu
M
Department of Pharmacology, Akita University School of Medicine, Akita 010-8543, Japan. mmura0123@hotmail.co.jp
Ohba
Takayoshi
T
Xu
Feng
F
Satoh
Eisaku
E
Miyoshi
Ichiro
I
Suzuki
Takashi
T
Takahashi
Yoichirou
Y
Takahashi
Eiki
E
Watanabe
Hiroyuki
H
Ono
Kyoichi
K
Sasano
Hironobu
H
Kasai
Noriyuki
N
Ito
Hiroshi
H
Iijima
Toshihiko
T
D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004558:Electric Stimulation; D004562:Electrocardiography; D006339:Heart Rate / Q000235:genetics; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D013564:Sympathetic Nervous System / Q000378:metabolism*
C500963:Cacna1b protein, mouse; C510225:Cacnb3 protein, mouse; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D002118:Calcium; D009638:Norepinephrine