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

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.