The PDZ Motif of {alpha}1C Subunit is not Required for Surface Trafficking and Adrenergic Modulation of CaV1.2 in Heart [Molecular Biophysics]

December 11th, 2014 by Yang, L., Katchman, A., Weinberg, R. L., Abrams, J., Samad, T., Wan, E., Pitt, G. S., Marx, S. O.

Voltage-gated Ca2+ channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts on trafficking, localization, turnover, and most importantly on multifaceted regulation of its function in the heart. Several studies hint at an important role for the C-terminus of the α1C subunit as a hub for multi-dimensional regulation of CaV1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C-terminus of α1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of CaV1.2 in neurons and in the efficient signaling to cAMP-response-element-binding protein (CREB) in neurons. The role of the α1c PDZ-ligand domain in the heart is however not known. To determine whether the α1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes we generated transgenic mice with inducible expression of a N-terminal FLAG-epitope tagged dihydropyridine-resistant α1C with the PDZ motif deleted (ΔPDZ). These mice were crossed with α-myosin heavy chain (αMHC) rtTA transgenic mice, and the double transgenic mice were fed doxycycline. The ΔPDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, providing functional evidence that they appropriately target to dyads. The ΔPDZ Ca2+ channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the α1C PDZ motif is not required for surface trafficking, localization to the dyad or adrenergic stimulation of CaV1.2 in adult cardiomyocytes.
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