Key result
Deletion of the PDZ motif of the α1C subunit did not alter surface trafficking, basal function, or adrenergic modulation of CaV1.2 channels in adult mouse cardiomyocytes.
The PDZ ligand motif of the α1C subunit is not required for surface trafficking, dyad localization, or adrenergic modulation of CaV1.2 channels in adult cardiomyocytes.
PDZ motif deletion is dispensable for CaV1.2 function in adult mouse cardiomyocytes; hypothesis-generating for trafficking mechanisms and requires validation in other models.
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 Ca V 1.2 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 α 1C subunit as a hub for multidimensional regulation of Ca V 1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C terminus of α 1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of Ca V 1.2 in neurons, and in the efficient signaling to cAMP-response element-binding protein in neurons. However, the role of the α 1C PDZ ligand domain in the heart is not known. To determine whether the α 1C PDZ motif is critical for Ca V 1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N-terminal FLAG epitope-tagged dihydropyridine-resistant α 1C with the PDZ motif deleted (ΔPDZ). These mice were crossed with α-myosin heavy chain reverse transcriptional transactivator 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, a dihydropyridine Ca 2+ channel blocker, providing functional evidence that they appropriately target to dyads. The ΔPDZ Ca 2+ channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the α 1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of Ca V 1.2 in adult cardiomyocytes.The mechanisms responsible for Ca V 1.2 regulation by the α 1C C terminus are unknown. Results Trafficking, basal function, and adrenergic modulation of Ca V 1.2 were not altered in cardiomyocytes of transgenic mice expressing PDZ-deleted α 1C . Conclusion PDZ-mediated interactions are not required for Ca V 1.2 trafficking and function in the heart. Significance The regulation of Ca V 1.2 by auxiliary proteins does not depend on the PDZ ligand motif in the heart.
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Yang et al. (2014) studied this question. Deletion of the PDZ motif of the α1C subunit (ΔPDZ) was evaluated on Trafficking, basal function, and adrenergic modulation of CaV1.2. Deletion of the PDZ motif of the α1C subunit did not alter surface trafficking, basal function, or adrenergic modulation of CaV1.2 channels in adult mouse cardiomyocytes.
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