The PDZ motif of the ?1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.
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ABSTRACT: Voltage-gated Ca(2+) 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 trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart. Several studies hint at an important role for the C terminus of the ?1C subunit as a hub for multidimensional 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 ?1C 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 in neurons. However, the role of the ?1C PDZ ligand domain in the heart is not known. To determine whether the ?1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N-terminal FLAG epitope-tagged dihydropyridine-resistant ?1C with the PDZ motif deleted (?PDZ). These mice were crossed with ?-myosin heavy chain reverse transcriptional transactivator transgenic mice, and the double-transgenic mice were fed doxycycline. The ?PDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, a dihydropyridine Ca(2+) channel blocker, providing functional evidence that they appropriately target to dyads. The ?PDZ Ca(2+) channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the ?1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of CaV1.2 in adult cardiomyocytes.
SUBMITTER: Yang L
PROVIDER: S-EPMC4303668 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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