Modified Sympathetic Nerve System Activity with Overexpression of the Voltage-dependent Calcium Channel β3 Subunit

• Published in: The Journal of biological chemistry Vol. 283; no. 36; pp. 24554 - 24560
• Main Authors: Murakami, Manabu, Ohba, Takayoshi, Xu, Feng, Satoh, Eisaku, Miyoshi, Ichiro, Suzuki, Takashi, Takahashi, Yoichirou, Takahashi, Eiki, Watanabe, Hiroyuki, Ono, Kyoichi, Sasano, Hironobu, Kasai, Noriyuki, Ito, Hiroshi, Iijima, Toshihiko
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.09.2008; American Society for Biochemistry and Molecular Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M802319200

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 β3 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 β3-overexpressing transgenic (β3-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 β3-null and CaV2.2 (α1B)-null mice. The β3-Tg mice showed increased expression of the β3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The β3-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 β3-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 β3-Tg mice, whereas β3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the β3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of β3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the β3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.