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 μm). The D1/D5 receptor agonist dihydrexidine (DHX) (0.01-10 μm; 5 min) or R-(+)SKF81291 (10 μm) 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⁺]_ichelation by BAPTA or inhibition of PKC by bisindolymaleimide (BiM1), but not inhibition of [Ca²⁺]_irelease 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 anN-[2-((o-bromocinamyl)amino)ethyl]-5-isoquinolinesulfonamide (H-89)- or internal PKA inhibitory peptide_[5-24]-sensitive (PKA-dependent) transient (∼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.