title: β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly.
abstract: Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and β-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and β-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, β-arrestin 1, and β-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. β-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P < .01). GRK2 expression was higher in PRLomas and NFPAs compared with GHomas (P < .05). In the GHoma group, GRK2 expression was inversely correlated to β-arrestin 1 (P < .05) and positively correlated to β-arrestin 2 (P < .0001). SSA treatment did not affect GRK2 and β-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, β-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, β-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, β-arrestin 1, and β-arrestin 2 expression in a representative number of pituitary adenomas. β-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment.
authors.affiliation: Erasmus Medical Center, Room Ee 530b, Doctor Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. l.hofland@erasmusmc.nl.
authors.forename: Federico
authors.initials: F
authors.lastname: Gatto
authors.forename: Richard
authors.initials: R
authors.lastname: Feelders
authors.forename: Rob
authors.initials: R
authors.lastname: van der Pas
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Fadime
authors.initials: F
authors.lastname: Dogan
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Aart-Jan
authors.initials: AJ
authors.lastname: van der Lelij
authors.forename: Sebastian J C M M
authors.initials: SJ
authors.lastname: Neggers
authors.forename: Francesco
authors.initials: F
authors.lastname: Minuto
authors.forename: Wouter
authors.initials: W
authors.lastname: de Herder
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: Diego
authors.initials: D
authors.lastname: Ferone
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D000172:Acromegaly / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605256:Arrb1 protein, rat; C000605257:Arrb2 protein, rat; D019390:Arrestins; D012333:RNA, Messenger; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D013004:Somatostatin; D054769:G-Protein-Coupled Receptor Kinase 2; D015282:Octreotide