Hippocampal dopamine/DRD1 signaling dependent on the ghrelin receptor
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The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Gαq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Gαq-PLC-IP3-Ca(2+) at the expense of canonical DRD1 Gαs cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling.
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- Authors
- Kern, A., Mavrikaki, M., Ullrich, C., Albarran-Zeckler, R., Brantley, A. F., & Smith, R. G.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Smith, Roy G.
- ORCID
- Mavrikaki, Maria
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 163
- Issue
- 5
- Pages
- 1176-1190
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4937825
- OpenAlex
- W2177725039
- Cited by
- 136
- References
- 59
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 10 · 2023: 16 · 2022: 16 · 2021: 21 · 2020: 14 · 2019: 12 · 2018: 10 · 2017: 12 · 2016: 8
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG019230)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- growth hormone secretagogue receptor, GHS-R1a, dopamine D1 receptor, hippocampus, receptor dimerization, Gαq signaling, CaMKII, synaptic plasticity, synaptic remodeling, memory, cAMP-independent signaling, heteromeric receptors
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Hippocampus, Memory, Neuronal Plasticity, Signal Transduction, Receptors, Dopamine D1, Mice, Receptors, Ghrelin
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