a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
- University of California, Davis, United States
- University of Iowa, United States
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 a1-adrenergic receptors (ARs). a1AR 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 a1AR 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 a1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via a1AR - Pyk2 - Src signaling regulates synaptic strength.
Data availability
Raw datasets are available on Dryad (https://doi.org/10.25338/B86G9K).
Article and author information
Author details
Madeline Nieves-Cintron
Funding
National Institutes of Health (R01 MH097887)
- Johannes W Hell
National Institutes of Health (RF1 AG055357)
- Johannes W Hell
National Institutes of Health (R01 HL098200)
- Manuel F Navedo
National Institutes of Health (R01 HL121059)
- Manuel F Navedo
National Institutes of Health (T32 GM099608)
- Peter B Henderson
National Institutes of Health (R01 NS123050)
- Madeline Nieves-Cintron
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Yukiko Goda, Okinawa Institute of Science and Technology, Japan
Ethics
Animal experimentation: All procedures followed NIH guidelines and had been approved by the Institutional Animal Care and Use Committees (IACUC) at UC Davis (Protocol #20673 and #22403).
Version history
- Received: April 21, 2022
- Preprint posted: July 3, 2022 (view preprint)
- Accepted: June 19, 2023
- Accepted Manuscript published: June 20, 2023 (version 1)
- Version of Record published: July 6, 2023 (version 2)
Copyright
© 2023, Man et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
eLife 12:e79648.
https://doi.org/10.7554/eLife.79648
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