GPCR regulation of L-type calcium channels in neurons

Kwun Nok Mimi Man

Neuromodulators such as norepinephrine (NE) and dopamine (DA) play crucial roles in the regulation of animal behaviors. NE mediates arousal and attention, and DA is required for the formation of behaviorally salient memories. NE and DA signal to neurons via adrenergic receptors (AR) and dopamine receptors, respectively. In my talk, I present data delineating the molecular mechanisms underlying how the α1AR and dopamine D1-like receptor regulate neuronal function through modulation of L-type calcium channel (LTCC) activity.
We identified the LTCC CaV1.2 as a principal target for Gq-coupled α1ARs. α1AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream of Pyk2, Src. Pyk2 and Src were associated with CaV1.2. In the model neuroendocrine PC12 cell line, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α1AR signaling and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by NE. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and α1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via α1AR – Pyk2 – Src signaling regulates synaptic strength.
We found that the CaV1.2 is also subjected to regulation by the dopamine D1-like receptor. In stark contrast to stimulation by the α1AR which acts at a distance from the channel, D1-like receptor stimulation increases L-type activity at close proximity to the channel. The regulation requires canonical Protein Kinase A signaling and phosphorylation of serine residue 1928 on the C-terminal tail of the pore-forming subunit of the channel. Proximity ligation assay shows that the dopamine D5 receptor is within 40 nm of CaV1.2. Our data shows the action of two crucial neuromodulators centering on the LTCC CaV1.2 to regulate neuronal function, albeit with distinct signaling features.


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