Modulation of histamine H₂ receptor signalling by G‐protein‐coupled receptor kinase 2 and 3

<jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>To evaluate the role of G‐protein‐coupled receptor kinases (GRK) in the desensitization of the histamine H<jats:sub>2</jats:sub> receptor, the H<jats:sub>2</jats:sub> receptor was transiently cotransfected with GRK2, 3, 5 or 6 in COS‐7 cells and the cyclic AMP levels in response to histamine were studied.</jats:p></jats:list-item> <jats:list-item><jats:p>Coexpression of the H<jats:sub>2</jats:sub> receptor with GRK2 and 3 significantly decreased both the basal cyclic AMP levels and the cyclic AMP response to 100 μ<jats:sc>M</jats:sc> histamine. Moreover, preincubation with 100 μ<jats:sc>M</jats:sc> histamine desensitized the H<jats:sub>2</jats:sub> receptor response to 53±8%. Coexpression of GRK2 and 3 increased the H<jats:sub>2</jats:sub> receptor desensitization to 27±4% and 24±4% respectively. No effect on either cyclic AMP response or desensitization was found when GRK5, GRK6 or dominant negative mutants of GRK2 or 3 (GRK2K<jats:sup>220</jats:sup>R and GRK3K<jats:sup>220</jats:sup>R) were coexpressed.</jats:p></jats:list-item> <jats:list-item><jats:p>To study the role of the C‐terminal tail in the GRK‐mediated desensitization of the H<jats:sub>2</jats:sub> receptor, three truncations of C‐tail were constructed: H<jats:sub>2</jats:sub>T295, H<jats:sub>2</jats:sub>T307 and H<jats:sub>2</jats:sub>T341. H<jats:sub>2</jats:sub>T307 and 341 H<jats:sub>2</jats:sub>T341 expressed and responded normally to 100 μ<jats:sc>M</jats:sc> histamine. The interaction of the H<jats:sub>2</jats:sub> receptor with GRK2 and 3 was also not altered upon truncation of the C‐terminal tail.</jats:p></jats:list-item> <jats:list-item><jats:p>These findings strongly suggest a role of GRK2 and 3 in the desensitization of the H<jats:sub>2</jats:sub> receptor. Furthermore, the finding that C‐terminal truncations of the H<jats:sub>2</jats:sub> receptor did not abolish the effect of GRK2 and 3 suggests that the C‐terminus is not involved in the GRK mediated desensitization of the histamine H<jats:sub>2</jats:sub> receptor.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2000) <jats:bold>131</jats:bold>, 1707–1715; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703676">10.1038/sj.bjp.0703676</jats:ext-link></jats:p>