Pharmacological and biochemical characterization of dopamine receptors mediating stimulation of a high affinity GTPase in rat striatum

Abstract

In synaptic plasma membranes of rat striatum, activation of dopamine receptors stimulates a high affinity GTPase activity. The rank order of potency of various dopamine receptor agonists in increasing GTP hydrolysis is the following: (-)-propylnorapomorphine greater than (-)-apomorphine = (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene [(+/-)-A-6,7-DTN] greater than dopamine = LY 171555 greater than noradrenaline. The selective D-1 dopamine receptor agonist, SKF 38393, does not produce a significant increase in GTP hydrolysis. Moreover, the dopamine-stimulated GTPase activity is completely reversed by the D-2 receptor antagonists, 1-sulpiride and zetidoline, but not by the selective D-1 antagonist SCH 23390. Na+ modulates the dopamine receptor-regulated GTP hydrolysis by increasing the percentage of stimulation and decreasing the agonist potency. Intrastriatal injection of pertussis toxin, which impairs the function of the inhibitory guanine nucleotide binding regulatory protein (Ni) of adenylate cyclase, significantly reduces the dopamine stimulation of striatal GTPase activity and the dopamine inhibition of adenylate cyclase. In contrast, cholera toxin, which blocks the stimulation of GTPase activity by hormones which increase adenylate cyclase activity, does not modify the dopamine-stimulated GTPase activity. These data indicate that the stimulation of GTPase activity elicited by dopamine results from activation of the D-2 type of dopamine receptors and is expression of the increased turnover of GTP at the level of Ni. The results are consistent with the idea that Ni is involved in the inhibitory coupling of striatal D-2 receptors to adenylate cyclase.