Σάββατο 12 Αυγούστου 2017

Adenosine and dopamine oppositely modulate a hyperpolarization activated current Ih in chemosensory neurons of the rat carotid body in co-culture

Abstract

Adenosine and dopamine (DA) act as neurotransmitters or neuromodulators at the carotid body (CB) chemosensory synapse, however, their mechanisms of action are not fully understood. Using a functional co-culture model of rat CB chemoreceptor (type I) cell clusters and juxtaposed afferent petrosal neurons (PNs), we tested the hypothesis that adenosine and DA act postsynaptically to modulate a hyperpolarization-activated, cyclic nucleotide-gated (HCN) cation current (Ih). In whole-cell recordings from hypoxia-responsive PNs, cAMP mimetics enhanced Ih whereas the HCN blocker ZD7288 (2 μm) reversibly inhibited Ih. Adenosine caused a potentiation of Ih (EC50 ∼ 35 nm) that was sensitive to the A2a blocker SCH58261 (5 nm), and an ∼16 mV depolarizing shift in V1/2 for voltage dependence of Ih activation. By contrast, DA (10 μm) caused an inhibition of Ih that was sensitive to the D2 blocker sulpiride (1–10 μm), and an ∼11 mV hyperpolarizing shift in V1/2. Sulpiride potentiated Ih in neurons adjacent to, but not distant from, type I cell clusters. DA also decreased PN action potential frequency whereas adenosine had the opposite effect. During simultaneous paired recordings, SCH58261 inhibited both the presynaptic hypoxia-induced receptor potential in type I cells and the postsynaptic PN response. By contrast, SCH58261 inhibited only the postsynaptic PN response induced by isohydric hypercapnia. Confocal immunofluorescence confirmed the localization HCN4 subunits in tyrosine hydroxylase-positive chemoafferent neurons in tissue sections of rat petrosal ganglia. These data suggest that adenosine and dopamine, acting through A2a and D2 receptors respectively, regulate PN excitability via their opposing actions on Ih.

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