The C terminal tail of the histamine H2 receptor contains positive and negative signals important for signal transduction and receptor down-regulation.

To examine the role of the C terminal tail in H 2 receptor regulation, three cDNAs, encoding truncated histamine H 2 receptor mutants (H 2 T295, H 2 T307, and H 2 T341), were constructed and stably transfected in Chinese hamster ovary (CHO) cells. The amino acids before position 307 appear to be necessary for proper receptor transport or folding, as no detectable H 2 receptor binding of the H 2 T295 was observed after transfection. Truncation of the C terminal tail by 51 amino acids (H 2 T307) did not affect the binding properties of H 2 antagonists and histamine or histamine-induced signaling. Yet, removal of 17 amino acids generated a mutant receptor (H 2 T341), which was able to form a ternary complex but was unable to fully activate the G s protein on histamine exposure. Agonist-induced but not the cyclic AMP-dependent H 2 receptor down-regulation was more profound for the H 2 T307 receptor, indicating that different structural elements of the H 2 receptor protein are involved in the cyclic AMP-dependent and independent pathways of H 2 receptor down-regulation. Taken together, in this study we identified regions in the C terminal tail of the H 2 receptor that act as positive and/or negative signals in H 2 receptor signaling and down-regulation.