Short‐term desensitization of the histamine H₁ receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways

Abstract

4 Neither the release component of the ATP response (50 jiM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 tIM histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 ± 33 nM; desensitized cells: 331 + 96 nM, n = 4, P < 0.05). 5 Activation of protein kinase C (PKC) by phorbol-12-myristate-1 3-acetate was found to inhibit the histamine as well as ATP-induced Ca2" response in a dose-dependent manner.6 In PKC downregulated cells the second phase of the histamine-induced Ca2+ response was significantly elevated, indicating the involvement of PKC in the negative feedback on the Ca2+ influx (control cells: second phase: 601 ± 52 nM (n = 11); PKC downregulated cells: second phase: 890 ± 90nM, n = I0, P<0.05).7 Homologous desensitization of H, receptor responsiveness was still observed in PKC downregulated cells, implying the rapid activation of a regulatory mechanism other than PKC.8 Based on our experimental data we suggest that short-term desensitization of the histamine H, receptor evolves from two different processes: a selective reduction of the histamine-induced Ca2+ release, mediated by a PKC-independent pathway, and a non-selective inhibition of the receptormediated Ca2+ influx activated by a PKC-dependent pathway.

Cumulated Ca2+ spike duration underlies Ca2+ oscillation frequency-regulated NFκB transcriptional activity

“…4D) (Dolmetsch et al, 1998). It has been well documented that the desensitization of histamine receptor is at least partially dependent on the activation and phosphorylation of PKC (Dickenson and Hill, 1993;Fujimoto et al, 1999;Ignesti et al, 1996;Smit et al, 1992;Warashina, 1997), as is the case for other types of membrane receptor (Dickenson et al, 1993;Yan et al, 1998).…”

Homologous and Heterologous Phosphorylations of Human Histamine H1 Receptor in Intact Cells

“…reported to decrease H1R signaling (12). Phorbol esterinduced decrease in H1R signaling was elimitated in a mutant H1R lacking putative PKC-catalyzed phosphorylation sites (14).…”

The effect of the PKC inhibitor GF109203X on the release of Ca2+ from internal stores and Ca2+ entry in DDT1 MF‐2 cells

“…Inhibition of PKC was shown to enhance the histamine and bradykinin induced formation of Ins(1,4,5)P3 in bovine adrenal chromaffin cells (Boarder & Challis, 1992). In contrast, an inhibitory feedback loop causing homologous desensitization of histamine evoked Ca2+ release was shown to be PKC-independent in HeLa cells (Smit et al, 1992). Recently, a positive feedback loop mediated by activation of PKC and modulating histamine and metacholine evoked Ca2+ metabolism was suggested in bovine tracheal cells .…”