Es. Nisenbaum et al., SELECTIVE BLOCKADE OF A SLOWLY INACTIVATING POTASSIUM CURRENT IN STRIATAL NEURONS BY (+ -)6-CHLORO-APB HYDROBROMIDE (SKF82958)/, Synapse, 29(3), 1998, pp. 213-224
The ion channels of rat striatal neurons are known to be modulated by
stimulation of D-1 dopamine receptors. The susceptibility of depolariz
ation-activated K+ currents to be modulated by the D-1 agonist, llyl-1
-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepine (APB) was investigated us
ing whole-cell voltage-clamp recording techniques from acutely isolate
d neurons. APE (0.01-100 mu M) produced a concentration-dependent redu
ction in the total K+ current. At intermediate concentrations (ca. 10
mu M), APE selectively depressed the slowly inactivating A-current (I-
AS). A similar effect was produced by application of the D-1 agonist,
roxy-1-phenyl-2,3,4,5-tetrahydro-1-H-2-benzazepine (SKF38393, 10 mu M)
. APB reduced I-AS rapidly, having onset and recovery time constants o
f 1.2 sec and 1.6 sec, respectively. Unexpectedly, the effect of APB c
ould not be mimicked by application of Sp-adenosine 3',5'-cyclic monop
hosphothioate triethylamine (Sp-cAMPS, 100-200 mu M), a membrane-perme
able analog of cyclic AMP (cAMP), or by pretreatment with forskolin (2
5 mu M), an activator of adenylyl cyclase. The reduction in IA, also w
as not blocked by pretreatment with the D-1 receptor antagonist, R(+)-
SCH23390 hydrochloride (SCH23390, 10-20 mu M). In addition, intracellu
lar dialysis with guanosine-5'-O-(2-thiodiphosphate(GDP-beta-S, 200 mu
M) did not preclude the APE-induced inhibition of I-AS, nor did dialy
sis with guanosine-5'-O-(3-thiotriphosphate (GTP-gamma-S, 400 mu M) pr
event reversal of the effect. The effect of APB was produced by a redu
ction in the maximal conductance of IA, without changing the voltage-d
ependence of the current. Collectively, these results argue that APE d
oes not inhibit I-AS through D-1 receptors coupled to stimulation of a
denylyl cyclase, but rather by allosterically regulating or blocking t
he channels giving rise to this current. (C) 1998 Wiley-Liss, Inc.