Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels

Voltage-Elated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha 1D subunit (D-LTCCs) are expressed in neurons and neuroendocrine cells. Their relative contribution to total L-type Ca2+ currents and their physiological role and significance as a drug target remain unknown. Therefore, we generated D-LTCC deficient mice (alpha 1D(-/-)) that were viable with no major disturbances of glucose metabolism. alpha 1D(-/-) mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wild-type controls, D-LTCC-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in alpha 1D(-/-) mice. We conclude that alpha 1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.