title: H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells.
abstract: The histamine H4 receptor (HRH4), discovered only 13 years ago, is considered a promising drug target for allergy, inflammation, autoimmune disorders and cancer, as reflected by a steadily growing number of scientific publications and patent applications. Although the presence of HRH4 has been evidenced in the testis, its specific localization or its role has not been established. Herein, we sought to identify the possible involvement of HRH4 in the regulation of Leydig cell function. We first evaluated its expression in MA-10 Leydig tumor cells and then assessed the effects of two HRH4 agonists on steroidogenesis and proliferation. We found that HRH4 is functionally expressed in MA-10 cells, and that its activation leads to the inhibition of LH/human chorionic gonadotropin-induced cAMP production and StAR protein expression. Furthermore, we observed decreased cell proliferation after a 24-h HRH4 agonist treatment. We then detected for the sites of HRH4 expression in the normal rat testis, and detected HRH4 immunostaining in the Leydig cells of rats aged 7-240 days, while 21-day-old rats also presented HRH4 expression in male gametes. Finally, we evaluated the effect of HRH4 activation on the proliferation of normal progenitor and immature rat Leydig cell culture, and both proved to be susceptible to the anti-proliferative effect of HRH4 agonists. Given the importance of histamine (2-(1H-imidazol-4-yl)ethanamine) in human (patho)physiology, continued efforts are directed at elucidating the emerging properties of HRH4 and its ligands. This study reveals new sites of HRH4 expression, and should be considered in the design of selective HRH4 agonists for therapeutic purposes.
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Adriana María Belén
authors.initials: AM
authors.lastname: Abiuso
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Berensztein
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Romina María
authors.initials: RM
authors.lastname: Pagotto
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Elba Nora
authors.initials: EN
authors.lastname: Pereyra
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Vanina
authors.initials: V
authors.lastname: Medina
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Diego José
authors.initials: DJ
authors.lastname: Martinel Lamas
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Marcos
authors.initials: M
authors.lastname: Besio Moreno
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina.
authors.forename: Omar Pedro
authors.initials: OP
authors.lastname: Pignataro
authors.affiliation: Laboratory of Molecular Endocrinology and Signal TransductionInstitute of Biology and Experimental Medicine, National Scientific and Technical Research Council (IByME-CONICET), CP 1428 Buenos Aires, ArgentinaResearch LaboratoryEndocrinology Service, Garrahan Pediatric Hospital, CP 1245 Buenos Aires, ArgentinaCell Biology UnitInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayLaboratory of RadioisotopesSchool of Pharmacy and Biochemistry, University of Buenos Aires, CP 1113 Buenos Aires, ArgentinaInstitute for Biomedical Research (BIOMED)School of Medical Sciences, Pontifical Catholic University of Argentina, National Scientific and Technical Research Council (UCA-CONICET), CP1107 Buenos Aires, ArgentinaDepartment of Biological ChemistrySchool of Sciences, University of Buenos Aires, CP 1428 Buenos Aires, Argentina carolina.mondillo@gmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Mondillo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003994:Bucladesine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D010091:Oximes / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013737:Testis / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D006063:Chorionic Gonadotropin; D006146:Guanidines; D017442:Histamine Agonists; C498828:Hrh4 protein, rat; D007211:Indoles; C000591334:JNJ28610244; D010091:Oximes; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D003994:Bucladesine; D000242:Cyclic AMP; D013890:Thiourea
keywords: H4 receptors; Leydig cells; histamine; steroidogenesis