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bioRxiv · 10.1101/2022.07.01.498400

α1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents

Man, K. N. M.·Henderson, P. B.·Kim, K.·Shi, M.·Zhang, M.·Nieves-Cintron, M.·Navedo, M. F.·Horne, M. C.·Hell, J. W.
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Abstract

The cellular mechanisms mediating norepinephrine functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV1.2 as a principal target for Gq- coupled 1-adrenergic receptors (ARs). 1AR 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 CaV1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by 1AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and 1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via 1AR - Pyk2 - Src signaling regulates synaptic strength.

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Man, K. N. M., Henderson, P. B., Kim, K., Shi, M., Zhang, M., Nieves-Cintron, M., Navedo, M. F., Horne, M. C., Hell, J. W.. 2022-07-03. α1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents. https://doi.org/10.1101/2022.07.01.498400

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