Dopamine D4 receptor mediated inhibition of potassium current in neurohypophysial nerve terminals

Dopamine influences the release of neurohypophysial peptides in vivo. However, the extent to which this effect is caused by a direct dopaminergic action within the neurohypophysis remains unclear. With use of the patch-clamp technique on thin slices of rat posterior pituitary glands, we now provide evidence that dopaminergic agonists inhibit potassium current (IK) in neurohypophysial nerve terminals. Superfusion with the dopamine receptor agonist, (+/-)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin (PPHT), causes a reversible inhibition of whole-terminal IK under voltage clamp. This effect is concentration-dependent, with a maximal inhibition of 40 +/- 5% and an EC50 of 1.8 +/- 1.0 microM. It can be blocked with either a nonselective D2-like antagonist (100 microM eticlopride) or with the highly selective D4 antagonist, RBI-257 (10 microM). U101958 (a derivative of RBI-257) exhibits agonist activity similar to PPHT. Neither SKF 38393 (a D1/D5 agonist) nor quinpirole (a D2/D3 agonist) had any effect on whole-terminal IK in this preparation. Kinetic analysis demonstrated that the amplitude of both the rapidly and slowly inactivating phases of neurohypophysial IK are reduced by D4 receptor activation. These two separate current components have previously been shown to represent current through two distinct potassium channels, an A-current channel and a high-conductance Ca++-activated K+ channel. Thus, both channel types can be modulated by D4 receptors. This effect is likely to enhance the release of neurohypophysial peptides in vivo.