α(1)-Adrenergic receptor–PKC–Pyk2–Src signaling boosts L-type Ca(2+) channel Ca(V)1.2 activity and long-term potentiation in rodents

The cellular mechanisms mediating norepinephrine (NE) 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 α(1)-adrenergic receptors (ARs). α(1)AR signaling increased LTCC activity in hippocampal neurons. This regulation required protein kinase C (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 NE. Indeed, a form of hippocampal long-term potentiation (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.