Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels.
Voltage-gated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha1D 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 (alpha1D-/-) that were viable with no major disturbances of glucose metabolism. alpha1D-/-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 alpha1D-/- mice. We conclude that alpha1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.
Institut für Biochemische Pharmakologie, Innsbruck, Austria.
J
J
Platzer
J
J
Engel
A
A
Schrott-Fischer
K
K
Stephan
S
S
Bova
H
H
Chen
H
H
Zheng
J
J
Striessnig
D000161:Acoustic Stimulation; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D003638:Deafness / Q000151:congenital* / Q000209:etiology; D004569:Electroencephalography; D004594:Electrophysiology; D006199:Hair Cells, Auditory, Inner / Q000502:physiology; D018072:Hair Cells, Auditory, Outer / Q000502:physiology; D006321:Heart / Q000503:physiopathology; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D011817:Rabbits; D012849:Sinoatrial Node / Q000503:physiopathology*
D020746:Calcium Channels, L-Type