Functional disorders of the sympathetic nervous system in mice lacking thealpha(1B) subunit (Ca-v 2.2) of N-type calcium channels

N-type voltage-dependent Ca2+ channels (VDCCs), predominantly localized in the nervous system, have been considered to play an essential role in a var iety of neuronal functions, including neurotransmitter release at sympathet ic: nerve terminals. As a direct approach to elucidating the physiological significance of N-type VDCCs, we have generated mice genetically deficient in the alpha (1B) subunit (Cav 2.2), The rule-deficient null mice, surprisi ngly, have a normal life span and are free from apparent behavioral defects . A complete and selective elimination of N-type currents, sensitive to ome ga -conotoxin GVIA, was observed without significant changes in the activit y of other VDCC types in neuronal preparations of mutant mice. The barorefl ex response, mediated by the sympathetic nervous system, was markedly reduc ed after bilateral carotid occlusion, In isolated left atria prepared from N-type-deficient mice, the positive inotropic responses to electrical sympa thetic neuronal stimulation were dramatically decreased compared with those of normal mice. In contrast, parasympathetic nervous activity in the mutan t mice was nearly identical to that of wild-type mice. Interestingly, the m utant mice showed sustained elevation of heart rate and blood pressure. The se results provide direct evidence that N-type VDCCs are indispensable for the function of the sympathetic nervous system in circulatory regulation an d indicate that N-type VDCC-deficient mice will be a useful model for study ing disorders attributable to sympathetic nerve dysfunction.