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Ca2+ Channel α1B Subunit (CaV 2.2) Knockout Mouse Reveals a Predominant Role of N-Type Channels in the Sympathetic Regulation of the Circulatory System

https://doi.org/10.1016/S1050-1738(02)00173-1Get rights and content

Abstract

N-type voltage-dependent Ca2+ 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, α1B subunit (CaV 2.2)-deficient mice were generated, in which peripheral neurons showed a complete and selective elimination of N-type channel currents sensitive to ω-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.

Section snippets

Selective and Complete Elimination of N-Type Channels by Disruption of α1B Subunit Gene

The Ca2+ channel classification, including “N type,” was initiated by Tsien and colleagues (Nowycky et al. 1985). “N type” was originally used to designate only the decaying component, whereas all the sustained components were grouped together as one L-type channel (Nowycky et al. 1985). Because the toxin suppressed both the decaying and sustained currents, both the N-type channel resistant to L-type channel blockers such as DHP and the L-type channel were reported to be susceptible to

Impaired Inotropic Contraction in Isolated Atria from N-Type-Deficient Mice

Sympathetic neurons have been considered to be a useful system in which to relate VDCC activity quantitatively with the downstream cellular response, that is, neurotransmitter release (Hirning et al. 1988). It is also well established that sympathetic nerves and parasympathetic nerves modulate the contractile force of atria in opposite directions: norepinephrine released from sympathetic nerve endings potentiates VDCC current through the β-adrenergic receptor stimulation to increase the atrial

Chronic Elevation of Blood Pressure and Heart Rate, and Impaired Baroreflex in N-Type Channel-Deficient Mice

N-type channel-deficient mice were expected to show hypotension, because previous reports demonstrated hypotension by administration of ω-CgTx-GVIA in animal models Bond and Boot 1992, Pruneau and Angus 1990. However, the genetic deficit of N-type VDCCs clearly led to higher levels of mAP and heart rate (HR) in our measurement of arterial blood pressure (AP) and HR in the carotid artery. Mean AP (mAP) and HR in knockout mice were 102.0 ± 4.3 mm Hg and 714.0 ± 11.5 beats per min (mean ± SE),

N-Type Knockout Mice as a Model for Autonomic Nervous Diseases

It is known that many patients suffering from primary autonomic failure show supine hypertension in addition to orthostatic hypotension Shannon et al. 1997, Vagaonescu et al. 2000. Because the mechanism of supine hypertension has not yet been fully clarified, it should be interesting to examine whether attenuation of sympathetic activity by downregulation of N-type VDCCs can be a cause of primary autonomic failure, because the N-type VDCC null mice showed hypertension and lack of baroreflex

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