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alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.
1Institut für Biochemische Pharmakologie, Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria.
The Journal of Biological Chemistry
|April 4, 2001
Summary
Alpha1D splice variants form distinct L-type Ca2+ channels (LTCCs) with unique properties. These D-LTCCs activate at more negative voltages and inactivate slower than C-LTCCs, impacting physiological processes.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiology
Background:
- L-type Ca2+ channels (LTCCs) are crucial for cellular functions.
- Alpha1D (D-LTCCs) and alpha1C (C-LTCCs) subunits form LTCCs with differing properties in inner hair cells (IHCs).
Purpose of the Study:
- To investigate the biophysical and pharmacological properties of cloned human alpha1D splice variants.
- To determine the extent to which alpha1D subunits dictate distinct LTCC characteristics.
Main Methods:
- Cloning and expression of human alpha1D splice variants in tsA-201 cells.
- Whole-cell patch-clamp recordings using Ba2+ as charge carrier.
- Radioligand binding assays to assess dihydropyridine (DHP) blocker interactions.
Main Results:
- The alpha1D(8A) splice variant produced functional LTCCs, while alpha1D(8B) did not yield intact protein or currents.
- Alpha1D(8A)-mediated currents activated at more negative potentials and inactivated slower than alpha1C-mediated currents.
- D-LTCCs exhibited an 8.5-fold lower sensitivity to the DHP blocker isradipine, attributed to voltage-dependent block rather than binding affinity.
Conclusions:
- Alpha1D(8A) subunits form slowly inactivating LTCCs that activate at more negative voltages compared to alpha1C.
- These distinct properties enable D-LTCCs to regulate physiological processes like sinoatrial node diastolic depolarization, IHC neurotransmitter release, and neuronal excitability.