a 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 functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV 1.2 as a principal target for Gq -coupled a1-adrenergic receptors (ARs). a1 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 CaV 1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV 1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by a1 AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV 1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and a1 AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV 1.2 activity via a1 AR - Pyk2 - Src signaling regulates synaptic strength.