Interaction of l‐Prolyl‐l‐Leucyl Glycinamide with Dopamine D2 Receptor: Evidence for Modulation of Agonist Affinity States in Bovine Striatal Membranes

Lalit K. Srivastava, Samina B. Bajwa, Rodney L. Johnson, Ram K. Mishra

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Abstract

The role of the hypothalamic tripeptide l‐prolyl‐l‐leucyl‐glycinamide (PLG) in modulating the agonist binding to bovine striatal dopamine D2 receptor was investigated using a selective high‐affinity agonist, n‐propylnor‐apomorphine (NPA). PLG caused an enhancement in [3H]NPA binding in striatal membranes in a dose‐dependent manner, the maximum effect being observed at 107106M concentration of the tripeptide. The Scat‐chard analysis of [3H]NPA binding to membranes preincu‐bated with 106M PLG revealed a significant increase in the affinity of the agonist binding sites. In contrast, there was no effect of PLG on the binding pattern of the antagonist [3H]spiroperidol. The antagonist versus agonist competition curves analyzed for agonist high‐ and low‐affinity states of the receptor displayed an increase in the population and affinity of the high‐affinity form of the receptor with PLG treatment. The low‐affinity sites concomitantly decreased with relatively small change in the affinity for the agonists. Almost similar results were obtained when either NPA or apomorphine was used in the competition experiments. A partial antagonistic effect of PLG on 5′‐guanylyl‐imidodiphosphate [Gpp(NH)p]‐induced inhibition of high‐affinity agonist binding was also observed, as the ratio of high‐ to low‐affinity forms of the receptor was significantly higher in the PLG‐treated membranes compared to the controls. Direct [3H]NPA binding experiments demonstrated that PLG attenuated the Gpp(NH)p‐induced inhibition of agonist binding by increasing the EC50 of the nu‐cleotide (concentration that inhibits 50% of the specific binding). No effect of PLG on high‐affinity [3H]NPA binding, however, could be observed when the striatal membranes were preincubated with Gpp(NH)p. The binding of antagonists and agonists to α2 adrenergic receptors, negatively coupled to adenylate cyclase in the striatum. was not affected by PLG. The results suggest that PLG modulates the affinity states of the dopamine D2 receptor, possibly by enhancing its interaction with the guanine nucleotide regulatory protein.

Original languageEnglish (US)
Pages (from-to)960-968
Number of pages9
JournalJournal of Neurochemistry
Volume50
Issue number3
DOIs
StatePublished - Mar 1988

Keywords

  • Agonist binding.
  • Dopamine D receptor
  • Guanine nucleotides
  • Melanocyte‐stimulating hormone release inhibiting factor
  • Striatum
  • l‐Prolyl‐l‐leucyl‐glycinamide

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