title: Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor.
abstract: 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.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: akern@scripps.edu.
authors.forename: Andras
authors.initials: A
authors.lastname: Kern
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mavrikaki
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Ullrich
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Rosie
authors.initials: R
authors.lastname: Albarran-Zeckler
authors.affiliation: Department of Neuroscience and Behavioral Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Alicia Faruzzi
authors.initials: AF
authors.lastname: Brantley
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: rgsmith@scripps.edu.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008568:Memory; D051379:Mice; D009473:Neuronal Plasticity; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004298:Dopamine; D017447:Receptors, Dopamine D1; D054440:Receptors, Ghrelin; C583261:Drd1 protein, mouse; C000592182:Ghsr protein, Mouse