title: Dopamine D1/D5 receptor modulates state-dependent switching of soma-dendritic Ca2+ potentials via differential protein kinase A and C activation in rat prefrontal cortical neurons.
abstract: To determine the nature of dopamine modulation of dendritic Ca2+ signaling in layers V-VI prefrontal cortex (PFC) neurons, whole-cell Ca2+ potentials were evoked after blockade of Na+ and K+ channels. Soma-dendritic Ca2+ spikes evoked by suprathreshold depolarizing pulses, which could be terminated by superimposed brief intrasomatic hyperpolarizing pulses, are blocked by the L-type Ca2+ channel antagonist nimodipine (1 microM). The D1/D5 receptor agonist dihydrexidine (DHX) (0.01-10 microM; 5 min) or R-(+)SKF81291 (10 microM) induced a prolonged (>30 min) dose-dependent peak suppression of these Ca2+ spikes. This effect was dependent on [Ca2+]i- and protein kinase C (PKC)-dependent mechanisms because [Ca2+]i chelation by BAPTA or inhibition of PKC by bisindolymaleimide (BiM1), but not inhibition of [Ca2+]i release with heparin or Xestospongin C, prevented the D1-mediated suppression of Ca2+ spikes. Depolarizing pulses subthreshold to activating a Ca2+ spike evoked a nimodipine-sensitive Ca2+ "hump" potential. D1/D5 stimulation induced an N-[2-((o-bromocinamyl)amino)ethyl]-5-isoquinolinesulfonamide (H-89)- or internal PKA inhibitory peptide[5-24]-sensitive (PKA-dependent) transient (approximately 7 min) potentiation of the hump potential to full Ca2+ spike firing. Furthermore, application of DHX in the presence of the PKC inhibitor BiM1 or internal PKC inhibitory peptide[19-36] resulted in persistent firing of full Ca2+ spike bursts, suggesting that a D1/D5-PKA mechanism switches subthreshold Ca2+ hump potential to fire full Ca2+ spikes, which are eventually turned off by a D1/D5-Ca2+-dependent PKC mechanism. This depolarizing state-dependent, D1/D5-activated, bi-directional switching of soma-dendritic L-type Ca2+ channels via PKA-dependent potentiation and PKC-dependent suppression may provide spatiotemporal regulation of synaptic integration and plasticity in PFC.
authors.affiliation: Neuroscience Discovery, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285-0510, USA.
authors.forename: Clint E
authors.initials: CE
authors.lastname: Young
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003712:Dendrites / Q000201:enzymology / Q000502:physiology; D004789:Enzyme Activation; D005071:Evoked Potentials; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017136:Ion Transport; D007700:Kinetics; D008297:Male; D009473:Neuronal Plasticity; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D017966:Pyramidal Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050641:Receptors, Dopamine D5
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C493607:Drd5 protein, rat; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015221:Potassium Channels; D018160:Receptors, Cytoplasmic and Nuclear; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D009553:Nimodipine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium