The human H₁ receptor gene expressed in Chinese hamster ovary cells (CHOhumH₁) encodes a classical histamine H₁ receptor with a pharmacology similar to that of the receptor found in guinea‐pig cerebellum and the endogenously expressed human H₁ receptor in 1321N1 astrocytoma cells as determined by [³H]‐mepyramine binding studies.

In CHOhumH₁ cells, histamine induced a concentration‐dependent rise in inositol phosphates (EC₅₀ 2.23±0.97 μm) and a rapid increase of [Ca²⁺]_i, followed by a sustained increase of [Ca²⁺]_i upon addition of 100 μm histamine.

Short‐term exposure of CHOhumH₁ cells to histamine (100 μm) resulted in a decrease of subsequent histamine‐induced Ca²⁺ responses. The histamine‐induced desensitization appeared to be heterologous as the ATP‐induced Ca²⁺ response was also found to be affected.

The process of heterologous histamine‐induced desensitization of the Ca²⁺ response in CHOhumH₁ cells can be ascribed to an alteration at the level of the intracellular Ca²⁺ pool, as the Ca²⁺ response of caffeine (10 mM), which releases Ca²⁺ from intracellular Ca²⁺ stores was also attenuated upon short‐term histamine exposure.

In CHOhumH₁ cells the PKC activator, PMA, was found to inhibit the histamine (100 μm)‐induced Ca²⁺ response concentration‐dependently (IC₅₀ 0.2±0.03 μm) as well as the ATP (100 μm)‐induced Ca²⁺ response. However, this inhibition was only partial and less effective than histamine‐pretreatment. Moreover, in CHOhumH₁ cells PKC downregulation induced by long‐term exposure to PMA (1 μm) did not affect the histamine‐induced desensitization nor did pretreatment with the specific PKC inhibitor Ro‐31–8220 (10 μm), indicating that in CHOhumH₁ cells PKC is probably not involved in the heterologous desensitization.

Long‐term treatment of CHOhumH₁ cells with histamine or other H₁ agonists resulted in a time‐ and concentration‐dependent decrease in the number of H₁ receptor binding sites (maximal reduction: 47±5%).

Long‐term exposure of CHOhumH₁ cells to ATP or PMA did not affect H₁ receptor density.

Both histamine (100 μm)‐ and ATP (100 μm)‐induced Ca²⁺ responses were affected upon long‐term exposure of cells to histamine (100 μm), which might be explained by an alteration at a level distant from the receptor.

These results show that in CHOhumH₁ cells the human histamine H₁ receptor is susceptible to short‐term and long‐term receptor regulation in which PKC does not seem to play a role. The CHOhumH₁ cells therefore provide an excellent model system for studying the mechanism(s) of PKC‐independent H₁ receptor regulation.