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Short-term desensitization of the histamine H1 receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways. 1992

M J Smit, and S M Bloemers, and R Leurs, and L G Tertoolen, and A Bast, and S W de Laat, and H Timmerman
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.

1. In this study we have investigated the effects of short-term exposure of cells to histamine on the subsequent H1 receptor responsiveness in HeLa cells, using Ca2+ fluorescence microscopy and video digital imaging. 2. In HeLa cells, histamine (100 microM) induces an immediate H1 receptor-mediated biphasic elevation of the intracellular Ca2+ concentration ([Ca2+]i) (basal [Ca2+]i: 81 +/- 30 nM, histamine-induced Ca2+ response: first phase: 1135 +/- 79 nM; second phase: 601 +/- 52 nM, n = 11). 3. The histamine H1 receptors on HeLa cells are readily susceptible to desensitization since repetitive exposure of the same group of cells to histamine (100 microM) markedly affected the release and influx component of the induced Ca2+ response (second application of histamine: first phase: 590 +/- 92 nM, second phase: 279 +/- 47 nM; third application of histamine: first phase: 454 +/- 127 nM, second phase: 240 +/- 45 nM, n = 6). Video digital imaging revealed an increase in the lag time between stimulation and monitoring of the Ca2+ response and a reduced increase in [Ca2+]i after desensitization with histamine. 4. Neither the release component of the ATP response (50 microM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 microM 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.

UI MeSH Term Description Entries
D011493 Protein Kinase C An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. Calcium Phospholipid-Dependent Protein Kinase,Calcium-Activated Phospholipid-Dependent Kinase,PKC Serine-Threonine Kinase,Phospholipid-Sensitive Calcium-Dependent Protein Kinase,Protein Kinase M,Calcium Activated Phospholipid Dependent Kinase,Calcium Phospholipid Dependent Protein Kinase,PKC Serine Threonine Kinase,Phospholipid Sensitive Calcium Dependent Protein Kinase,Phospholipid-Dependent Kinase, Calcium-Activated,Serine-Threonine Kinase, PKC
D011969 Receptors, Histamine H1 A class of histamine receptors discriminated by their pharmacology and mode of action. Most histamine H1 receptors operate through the inositol phosphate/diacylglycerol second messenger system. Among the many responses mediated by these receptors are smooth muscle contraction, increased vascular permeability, hormone release, and cerebral glyconeogenesis. (From Biochem Soc Trans 1992 Feb;20(1):122-5) H1 Receptor,Histamine H1 Receptors,H1 Receptors,Histamine H1 Receptor,Receptors, H1,H1 Receptor, Histamine,H1 Receptors, Histamine,Receptor, H1,Receptor, Histamine H1
D002110 Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes SMOOTH MUSCLE, stimulates CARDIAC MUSCLE, stimulates DIURESIS, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide PHOSPHODIESTERASES, antagonism of ADENOSINE RECEPTORS, and modulation of intracellular calcium handling. 1,3,7-Trimethylxanthine,Caffedrine,Coffeinum N,Coffeinum Purrum,Dexitac,Durvitan,No Doz,Percoffedrinol N,Percutaféine,Quick-Pep,Vivarin,Quick Pep,QuickPep
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa Cell
D006632 Histamine An amine derived by enzymatic decarboxylation of HISTIDINE. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. Ceplene,Histamine Dihydrochloride,Histamine Hydrochloride,Peremin
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D013755 Tetradecanoylphorbol Acetate A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA. Phorbol Myristate Acetate,12-Myristoyl-13-acetylphorbol,12-O-Tetradecanoyl Phorbol 13-Acetate,Tetradecanoylphorbol Acetate, 4a alpha-Isomer,12 Myristoyl 13 acetylphorbol,12 O Tetradecanoyl Phorbol 13 Acetate,13-Acetate, 12-O-Tetradecanoyl Phorbol,Acetate, Phorbol Myristate,Acetate, Tetradecanoylphorbol,Myristate Acetate, Phorbol,Phorbol 13-Acetate, 12-O-Tetradecanoyl,Tetradecanoylphorbol Acetate, 4a alpha Isomer

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