α1-Adrenergic receptor-PKC-Pyk2-Src signaling boosts L-type Ca2+ channel CaV1.2 activity and long-term potentiation in rodents

Abstract

The cellular mechanisms mediating norepinephrine (NE) functions in brain to result in behaviors are unknown. We identified the L-type Ca²⁺ channel (LTCC) Ca_V1.2 as a principal target for G_q-coupled α₁-adrenergic receptors (ARs). α₁AR 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_V1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of Ca_V1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α₁AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that Ca_V1.2 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 α₁AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of Ca_V1.2 activity via α₁AR-Pyk2-Src signaling regulates synaptic strength.

Keywords: L-type calcium channels; long-term potentiation; mouse; neuroscience; protein kinase C; tyrosine phosphorylation; α1-adrenergic receptor.