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Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels
J Platzer1, J Engel, A Schrott-Fischer
1Institut für Biochemische Pharmakologie, Innsbruck, Austria.
Abstract:
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.
Insights
The alpha1D subunit forms voltage-gated L-type Ca2+ channels (LTCCs) crucial for hearing and heart rhythm. Mice lacking alpha1D (alpha1D-/-) exhibited deafness and sinoatrial node dysfunction, highlighting D-LTCCs
Area of Science:
- Neuroscience
- Cardiology
- Genetics
Background:
- Voltage-gated L-type Ca2+ channels (LTCCs) with the alpha1D subunit (D-LTCCs) are found in neurons and neuroendocrine cells.
- The specific role and physiological significance of D-LTCCs remain largely uncharacterized.
- Their potential as therapeutic drug targets is yet to be determined.
Purpose of the Study:
- To investigate the physiological role of D-LTCCs in vivo.
- To determine the contribution of the alpha1D subunit to LTCC function in auditory and cardiac systems.
- To establish the significance of D-LTCCs in normal physiological processes.
Main Methods:
- Generation and analysis of alpha1D-deficient (alpha1D-/-) mice.
- Electrophysiological recordings in cochlear hair cells.
- Electrocardiogram (ECG) monitoring to assess cardiac function.
Main Results:
- Alpha1D-/- mice were viable and showed no major metabolic disturbances.
- Complete absence of L-type currents and hair cell degeneration led to deafness in alpha1D-/- mice.
- Sinoatrial node dysfunction, including bradycardia and arrhythmia, was observed in alpha1D-/- mice.
Conclusions:
- The alpha1D subunit forms functional LTCCs with unique properties, including negative activation thresholds.
- D-LTCCs are essential for maintaining normal auditory function.
- D-LTCCs play a critical role in regulating cardiac pacemaker activity.
