Phosphorylation of Ser¹⁹²⁸ mediates the enhanced activity of the L-type Ca²⁺ channel Ca_v1.2 by the β₂-adrenergic receptor in neurons

The L-type Ca²⁺ channel Ca_v1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving b-adrenergic receptors (bARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser¹⁹²⁸ in Ca_v1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser¹⁹²⁸ is not required for regulation of cardiac Ca_v1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Ca_v1.2 and enhancement of its activity by the β₂-adrenergic receptor (β₂AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Ca_v1.2 by PKA in cardiomyocytes and hippocampal neurons.