α₁ adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca²⁺ channel Ca_v1.2 activity and long-term potentiation in rodents

ABSTRACT The cellular mechanisms mediating norepinephrine functions in brain to result in behaviors are unknown. We identified the L-type Ca 2+ channel (LTCC) Ca V 1.2 as a principal target for G q - coupled α1-adrenergic receptors (ARs). α 1 AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with Ca V 1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of Ca V 1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α 1 AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that Ca V 1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and α 1 AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of Ca V 1.2 activity via α 1 AR - Pyk2 - Src signaling regulates synaptic strength.