Contribution of Serine Residues to Constitutive and Agonist-Induced Signaling via the D2S Dopamine Receptor: Evidence for Multiple, Agonist-Specific Active Conformations

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Vol. 54, Issue 2, 435-444, August 1998

Contribution of Serine Residues to Constitutive and Agonist-Induced Signaling via the D_2S Dopamine Receptor: Evidence for Multiple, Agonist-Specific Active Conformations

Brenda L. Wiens, Cole S. Nelson, and Kim A. Neve

Medical Research Service, Veterans Affairs Medical Center (B.L.W., K.A.N.), Departments of Behavioral Neuroscience (B.L.W., K.A.N.) and Physiology and Pharmacology (C.S.N., K.A.N.), and Center for Research on Occupational and Environmental Toxicology (C.S.N.), Oregon Health Sciences University, Portland, Oregon 97201

Dopamine D₂ receptors contain a cluster of serine residues in the fifth transmembrane domain that contribute to activationof the receptor as well as to the binding of agonists. We usedrat D_2S dopamine receptor mutants, each containing a serine-to-alaninesubstitution (S193A, S194A, S197A), to investigate the mechanismthrough which these residues affect activation of the receptor.Activation of the mutant receptor S194A was abolished in an agonist-dependentmanner, such that dopamine no longer inhibited cAMP accumulationin C6 glioma cells or activated G protein-regulated K⁺ channels in Xenopus laevis oocytes, whereas the efficacy of severalother agonists was unaffected. Dihydrexidine did not inhibit cAMPaccumulation at either S193A or S194A. The decreased efficacyof dihydrexidine at S193A and S194A and dopamine at S194A wasassociated with a decreased ability to detect a GTP-sensitivehigh affinity binding state for these agonists. The ability ofdopamine to stimulate [³⁵S]guanosine-5'-O-(3-thio)triphosphate binding via S194A also wasdecreased by ~50%. Finally, constitutive stimulation of [³⁵S]guanosine-5'-O-(3-thio)triphosphate binding and inhibition ofadenylate cyclase by the D_2S receptor was reduced by mutationof either S193 or S194. These data support the existence of multipleactive receptor conformations that are differentially sensitiveto mutation of serine residues in the fifth-transmembrane domain.

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