D1/D5 dopamine receptors stimulate intracellular calcium release in primary cultures of neocortical and hippocampal neurons.
D1/D5 dopamine receptors in basal ganglia, hippocampus, and cerebral cortex modulate motor, reward, and cognitive behavior. Previous work with recombinant proteins revealed that in cells primed with heterologous G(q/11)-coupled G-protein-coupled receptor (GPCR) agonists, the typically G(s)-linked D1/D5 receptors can stimulate robust release of calcium from internal stores when coexpressed with calcyon. To learn more about the intracellular signaling mechanisms underlying these D1/D5 receptor regulated behaviors, we explored the possibility that endogenous receptors stimulate internal release of calcium in neurons. We have identified a population of neurons in primary cultures of hippocampus and neocortex that respond to D1/D5 dopamine receptor agonists with a marked increase in intracellular calcium (Ca) levels. The D1/D5 receptor stimulated responses occurred in the absence of extracellular Ca(2+) indicating the rises in Ca involve release from internal stores. In addition, the responses were blocked by D1/D5 receptor antagonists. Further, the D1/D5 agonist-evoked responses were state dependent, requiring priming with agonists of G(q/11)-coupled glutamate, serotonin, muscarinic, and adrenergic receptors or with high external K(+) solution. In contrast, D1/D5 receptor agonist-evoked Ca(2+) responses were not detected in neurons derived from striatum. However, D1/D5 agonists elevated cAMP levels in striatal cultures as effectively as in neocortical and hippocampal cultures. Further, neither forskolin nor 8-Br-cAMP stimulation following priming was able to mimic the D1/D5 agonist-evoked Ca(2+) response in neocortical neurons indicating that increased cAMP levels are not sufficient to stimulate Ca release. Our data suggest that D1-like dopamine receptors likely modulate neocortical and hippocampal neuronal excitability and synaptic function via Ca(2+) as well as cAMP-dependent signaling.
Lezcano
Nelson
N
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-2300, USA.
Bergson
Clare
C
D000818:Animals; D000831:Animals, Newborn; D001552:Benzazepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D050641:Receptors, Dopamine D5; D012996:Solutions / Q000494:pharmacology
D001552:Benzazepines; D018491:Dopamine Agonists; C493607:Drd5 protein, rat; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D017447:Receptors, Dopamine D1; D012996:Solutions; D050641:Receptors, Dopamine D5; C067113:SK&F 81297; D000242:Cyclic AMP; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D011188:Potassium; D002118:Calcium