Selective blockade of a slowly inactivating potassium current in striatal neurons by (±) 6‐chloro‐APB hydrobromide (SKF82958)

Abstract

The ion channels of rat striatal neurons are known to be modulated by stimulation of D1 dopamine receptors. The susceptibility of depolarization-activated K+ currents to be modulated by the D1 agonist, 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepine (APB) was investigated using whole-cell voltage-clamp recording techniques from acutely isolated neurons. APB (0.01–100 μM) produced a concentration-dependent reduction in the total K+ current. At intermediate concentrations (ca. 10 μM), APB selectively depressed the slowly inactivating A-current (IAs). A similar effect was produced by application of the D1 agonist, 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1-H-2-benzazepine (SKF38393, 10 μM). APB reduced IAs rapidly, having onset and recovery time constants of 1.2 sec and 1.6 sec, respectively. Unexpectedly, the effect of APB could not be mimicked by application of Sp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (Sp-cAMPS, 100–200 μM), a membrane-permeable analog of cyclic AMP (cAMP), or by pretreatment with forskolin (25 μM), an activator of adenylyl cyclase. The reduction in IAs also was not blocked by pretreatment with the D1 receptor antagonist, R(+)-SCH23390 hydrochloride (SCH23390, 10–20 μM). In addition, intracellular dialysis with guanosine-5′-O-(2-thiodiphosphate (GDP-β-S, 200 μM) did not preclude the APB-induced inhibition of IAs, nor did dialysis with guanosine-5′-O-(3-thiotriphosphate (GTP-γ-S, 400 μM) prevent reversal of the effect. The effect of APB was produced by a reduction in the maximal conductance of IAs without changing the voltage-dependence of the current. Collectively, these results argue that APB does not inhibit IAs through D1 receptors coupled to stimulation of adenylyl cyclase, but rather by allosterically regulating or blocking the channels giving rise to this current. Synapse 29:213–224, 1998. © 1998 Wiley-Liss, Inc.