Role of G Protein-Coupled Receptor Kinases in the Homologous Desensitization of the Human and Mouse Melanocortin 1 Receptors

The human melanocortin 1 receptor (MC1R) undergoes homologous desensitization in melanoma cells.

• Desensitization of MC1R is agonist dose-dependent and not reliant on protein kinase A, protein kinase C, calcium mobilization, or MAPKs.
• Melanoma cells and normal melanocytes express GRK2 and GRK6, members of the G protein-coupled receptor kinase family.
• Cotransfection experiments show that both GRK2 and GRK6 can impair agonist-dependent signaling by MC1R or its mouse counterpart, Mc1r.
• GRK6, unlike GRK2, inhibits MC1R agonist-independent signaling.
• Expression of a dominant negative GRK2 mutant in melanoma cells enhances their cAMP response to agonists.
• Stable transfection of melanoma cells with GRK6 leads to decreased agonist-stimulated cAMP production.

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