α<sub>1</sub>-Adrenergic receptor-PKC-Pyk2-Src signaling boosts L-type Ca<sup>2+</sup> channel Ca<sub>V</sub>1.2 activity and long-term potentiation in rodents.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37338965.
- Also identified by DOI 10.7554/eLife.79648 and PMC identifier 10325713.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The cellular mechanisms mediating norepinephrine (NE) functions in brain to result in behaviors are unknown. We identified the L-type Ca<sup>2+</sup> channel (LTCC) Ca<sub>V</sub>1.2 as a principal target for G<sub>q</sub>-coupled α<sub>1</sub>-adrenergic receptors (ARs). α<sub>1</sub>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<sub>V</sub>1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of Ca<sub>V</sub>1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α<sub>1</sub>AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that Ca<sub>V</sub>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<sub>1</sub>AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of Ca<sub>V</sub>1.2 activity via α<sub>1</sub>AR-Pyk2-Src signaling regulates synaptic strength.
Medical subject headings
- Focal Adhesion Kinase 2
- Long-Term Potentiation