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

摘要

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-(+) (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⁺]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 (∼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.