{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T06:03:19Z","timestamp":1769148199847,"version":"3.49.0"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,8,15]],"date-time":"2013-08-15T00:00:00Z","timestamp":1376524800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,9]]},"abstract":"Background and Purpose<\/jats:title>An alanine to valine exchange at amino acid position 280 (A280V<\/jats:styled-content>) in the third intracellular loop of the human histamine H3<\/jats:sub><\/jats:styled-content> receptor was first identified in a patient suffering from S<\/jats:styled-content>hy\u2013D<\/jats:styled-content>rager syndrome and later reported as a risk factor for migraine. Here, we have compared the pharmacological and signalling properties of wild\u2010type (hH3<\/jats:sub>RWT<\/jats:sub><\/jats:styled-content>) and A280V<\/jats:styled-content> mutant (hH3<\/jats:sub>RA280V<\/jats:sub><\/jats:styled-content>) receptors stably expressed in CHO\u2010K1<\/jats:styled-content> cells.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>The hH3<\/jats:sub>RA280V<\/jats:sub> cDNA<\/jats:styled-content> was created by overlapping extension PCR<\/jats:styled-content> amplification. Receptor expression and affinity were assessed by radioligand (N<\/jats:styled-content>\u2010\u03b1\u2010[methyl\u20103<\/jats:sup>H<\/jats:styled-content>]\u2010histamine) binding to cell membranes, and receptor function by the inhibition of forskolin\u2010induced cAMP<\/jats:styled-content> accumulation and stimulation of ERK1<\/jats:styled-content>\/2 phosphorylation in intact cells, as well as stimulation of [35<\/jats:sup>S<\/jats:styled-content>]\u2010GTP<\/jats:styled-content>\u03b3S<\/jats:styled-content> binding to cell membranes.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Both receptors were expressed at similar levels with no significant differences in their affinities for H3<\/jats:sub><\/jats:styled-content> receptor ligands. Upon activation the hH3<\/jats:sub>RWT<\/jats:sub><\/jats:styled-content> was significantly more efficacious to inhibit forskolin\u2010induced cAMP<\/jats:styled-content> accumulation and to stimulate [35<\/jats:sup>S<\/jats:styled-content>]\u2010GTP<\/jats:styled-content>\u03b3S<\/jats:styled-content> binding, with no difference in pEC50<\/jats:sub><\/jats:styled-content> estimates. The hH3<\/jats:sub>RWT<\/jats:sub><\/jats:styled-content> was also more efficacious to stimulate ERK1<\/jats:styled-content>\/2 phosphorylation, but this difference was not significant. The inverse agonist ciproxifan was more efficacious at hH3<\/jats:sub>RWT<\/jats:sub><\/jats:styled-content> to reduce [35<\/jats:sup>S<\/jats:styled-content>]\u2010GTP<\/jats:styled-content>\u03b3S<\/jats:styled-content> binding but, for both receptors, failed to enhance forskolin\u2010induced cAMP<\/jats:styled-content> accumulation.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>The A280V<\/jats:styled-content> mutation reduces the signalling efficacy of the human H3<\/jats:sub><\/jats:styled-content> receptor. This effect may be relevant to the pathophysiology of disorders associated with the mutation.<\/jats:p><\/jats:sec>Linked Articles<\/jats:title>This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http:\/\/dx.doi.org\/\n10.1111\/bph.2013.170.issue\u20101<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12257","type":"journal-article","created":{"date-parts":[[2013,5,28]],"date-time":"2013-05-28T11:39:24Z","timestamp":1369741164000},"page":"127-135","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A single\u2010point mutation (Ala280Val<\/scp>) in the third intracellular loop alters the signalling properties of the human histamine H3<\/sub><\/scp> receptor stably expressed in CHO\u2010K1<\/scp> cells"],"prefix":"10.1111","volume":"170","author":[{"given":"Cecilia","family":"Flores\u2010Clemente","sequence":"first","affiliation":[{"name":"Departamento de Fisiolog\u00eda Biof\u00edsica y Neurociencias Centro de Investigaci\u00f3n y de Estudios Avanzados (Cinvestav) del IPN M\u00e9xico M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang\u00e9lica","family":"Osorio\u2010Espinoza","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda Biof\u00edsica y Neurociencias Centro de Investigaci\u00f3n y de Estudios Avanzados (Cinvestav) del IPN M\u00e9xico M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Escamilla\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda Biof\u00edsica y Neurociencias Centro de Investigaci\u00f3n y de Estudios Avanzados (Cinvestav) del IPN M\u00e9xico M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecules, Medicines and Systems Department of Medicinal Chemistry VU University Amsterdam Amsterdam The 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