A Seven Amino Acid Long Region in the Cardiac Cav1.2, Encompassing Ser1487, Is Essential for Mice Embryonic Development and “Fight or Flight” Responses

The cardiac calcium channel Cav1.2 is essential for embryonic development, cardiac excitation–contraction coupling, and the “Fight or Flight” response. Regulation of Cav1.2 by protein kinase A (PKA) phosphorylation is critical to this process, though the underlying mechanism remains contentious. We previously identified serine 1458 (S1458) in the proximal C-terminus of the human Cav1.2 as essential for PKA-mediated regulation in vitro. To investigate its functional role in vivo, we generated three mouse models targeting S1487, the mouse equivalent of human S1458. Comprehensive phenotyping and assessment of responses to β-adrenergic receptor stimulation were conducted in vivo, ex vivo, and in vitro. We demonstrate for the first time that a seven amino acid (7aa) region containing S1487 is crucial for proper channel folding, as homozygous mutant mice exhibited embryonic lethality. We confirm that phosphorylation at S1487 is necessary for altered Cav1.2 function required for the “Fight or Flight” response, clarifying the functional significance of this region.