title: The non-genomic rapid acidification in peripheral T cells by progesterone depends on intracellular calcium increase and not on Na+/H+-exchange inhibition.
abstract: Progesterone is an endogenous immunomodulator that is able to suppress T cell activation during pregnancy. An increased intracellular free calcium concentration ([Ca(2+)](i)), acidification, and an inhibition of Na(+)/H(+)-exchange 1 (NHE1) are associated with this progesterone rapid non-genomic response that involves plasma membrane sites. Such acidification, when induced by phytohemagglutinin, is calcium dependent in PKC down-regulated T cells. We investigated the relationship between this rapid response involving the [Ca(2+)](i) increase and various membrane progesterone receptors (mPRs). In addition, we explored whether the induction of acidification in T cells by progesterone is a direct result of the [Ca(2+)](i) increase. The results show that the intracellular calcium elevation caused by progesterone is inhibited by SKF96365, U73122, and 2-APB, but not by pertussis toxin or U73343. The elevation is enhanced by the protein tyrosine kinase inhibitor staurosporine and the protein kinase C inhibitors Ro318220 and Go6983. These findings suggest that progesterone does not stimulate the [Ca(2+)](i) increase via the Gi coupled mPR(α). Furthermore, progesterone-induced acidification was found to be dependent on Ca(2+) entry and blocked by the inorganic channel blocker, Ni(2+). However, BAPTA, an intracellular calcium chelator, was found to prevent progesterone-induced acidification but not the inhibition of NHE1. This implies that acidification by progesterone is a direct result of the [Ca(2+)](i) increase and does not directly involve NHE1. Taken together, further investigations are needed to explore whether one or more mPRs or PGRMC1 are involved in bringing about the T cell rapid response that results in the [Ca(2+)](i) increase and inhibition of NHE1.
authors.affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Jung-Nien
authors.initials: JN
authors.lastname: Lai
authors.forename: Olivia Ya-Hsuan
authors.initials: OY
authors.lastname: Wang
authors.forename: Veronica Hui-Chen
authors.initials: VH
authors.lastname: Lin
authors.forename: Ching-Fong
authors.initials: CF
authors.lastname: Liao
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Tarng
authors.forename: Eileen Jea
authors.initials: EJ
authors.lastname: Chien
mesh_terms: D000328:Adult; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009532:Nickel / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D002614:Chelating Agents; D004963:Estrenes; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011760:Pyrrolidinones; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D011374:Progesterone; D004533:Egtazic Acid; D009532:Nickel; C109986:2-aminoethoxydiphenyl borate; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019311:Staurosporine; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium