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WATER AND ELECTROLYTE HOMEOSTASIS

Involvement of G protein-coupled receptor kinase 4 and 6 in rapid desensitization of dopamine D₁ receptor in rat IEC-6 intestinal epithelial cells

¹Institute of Pharmacology and Therapeutics, Faculty of Medicine, 4200–319 Porto, Portugal; and ²Department of Pediatrics, Georgetown University Medical Center, Washington, District of Columbia 20007

Submitted 29 March 2004 ; accepted in final form 25 May 2004

Dopamine-induced inhibition of Na⁺-K⁺-ATPase has been suggested to play a role in the regulation of Na⁺ absorption at the intestinal level, and these effects were mediated by dopamine D₁-like receptors. The aim of this work was to evaluate the effect of the activation of the D₁-like receptors on the activity of the Na⁺/H⁺ exchanger (NHE) in the rat intestinal epithelial cell line IEC-6. The presence of D₁ receptors was confirmed by immunoblotting. The dopamine D₁-like receptor agonist SKF-38393 produced a concentration-dependent inhibition of NHE activity and stimulation of adenylyl cyclase (AC), this being antagonized by the D₁ selective antagonist SKF-83566. Effects of SKF-38393 on NHE and AC activities were maximal at 5 min of exposure to the agonist and rapidly diminished with no effect at 25 min. Exposure of cells for 25 min to dibutyryl-cAMP (0.5 mM) or to the AC activator forskolin (3 µM) effectively inhibited NHE activity. Pretreatment of cells with heparin (1 µM), a nonselective G protein-coupled receptor kinase (GRK) inhibitor, prevented the loss of effects on NHE activity after 25 min exposure to SKF-38393. The presence of GRK4, GRK6A, and GRK6B was confirmed by immunoblotting. Overnight treatment with the anti-GRK4–6 antibody complexed with Lipofectin was also effective in preventing loss of the effects of SKF-38393 on NHE and AC activities. It is concluded that dopamine D₁ receptors in IEC-6 rapidly desensitize to D₁-like agonist stimulation and GRK4 and 6 appear to be involved in agonist-mediated responsiveness and desensitization.

Na⁺/H⁺ exchanger; adenylyl cyclase

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