ライフサイエンスコーパス: GHS

1 GHS is caused by altered expression of genes encoding ne

2 GHS x WKY rats were backcrossed to breed for congenic ra

3 GHS-R1a antagonism has therefore been proposed as a pote

4 GHS-R1a signals through Gq, Gi/o, G13, and arrestin.

5 GHS-R1a-G-protein coupling and the formation of GHS-R1a:

6 Two human GPC-Rs related to both the type 1a GHS-R and NT-Rs were cloned and characterized.

7 the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) re

8 the growth hormone secretagogue receptor 1a (GHS-R1a), is a G-protein-coupled receptor that is differ

9 eceptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary.

10 rowth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of

11 rowth hormone secretagogue receptor type 1a (GHS-R1a), is considered to be the active form for its or

12 rowth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regula

13 rmed residuals in urinary calcium in an F(2) GHS x WKY mapping cohort.

14 hich suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secre

15 e was confirmed by treating MENX rats with a GHS-R1a antagonist.

16 However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that medi

17 de that stimulates food intake by activating GHS-R1A receptors in the hypothalamus.

18 All GHS rats received a fixed amount of a standard 1.2% calc

19 d 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and GHS rats have increased renal vitamin D receptor content

20 f DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of

21 supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated c

22 The relevance of ghrelin and GHS-R expression was verified in clinically relevant tis

23 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg x kg(-1) x d(-1), n=9); and (3)

24 Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hipp

25 f 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed an

26 This demonstrates that bias at GHS-R1a signaling can occur not only with regard to agon

27 ast 1 note (84% at BIDMC, 82% [corrected] at GHS, and 47% at HMC).

28 To delineate ligand selectivity at GHS-R1a signaling, we analyzed in detail the efficacy of

29 the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS

30 and the CNS penetrant inverse agonist 38 (AZ-GHS-38).

31 Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have be

32 an Galpha(q11) requires interactions between GHS-R1a and SST receptor subtype 5 (SST5) and that in th

33 Biasing GHS-R1a signaling with specific ligands may lead to the

34 shortest ghrelin analogue capable of binding GHS-R1a with better affinity than ghrelin(1-28).

35 3 administration increased renal CaR in both GHS and NC rats.

36 s effect on insulin secretion is mediated by GHS-R in pancreatic beta-cells.

37 s mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6.9 (95% CI 3.3 to 10.6) for pembroliz

38 wth hormone secretagogue receptor-deficient (GHS-R-deficient) mice displayed enhanced age-associated

39 tion of the GHS-R by structurally dissimilar GHSs, was conserved in GPR38 and GPR39.

40 pound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinica

41 on inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerti

42 fication of a genomic clone encoding a first GHS-R/NT-R family member (GPR38).

43 ix to 8 weeks later, rats were evaluated for GHS and tissue was collected for molecular experiments.

44 for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning,

45 sed to produce rats that were homozygous for GHS loci in the HC1 region between markers D1Mit2 and D1

46 In our search for GHS-R family members, we recently described the cloning

47 The genetic hypercalciuric stone-forming (GHS) rat is an animal model that closely resembles human

48 The genetic hypercalciuric stone-forming (GHS) rat model displays complex changes in physiology in

49 female genetic hypercalciuric stone-forming (GHS) rats (Rattus norvegicus) had higher coefficients of

50 ria in genetic hypercalciuric stone-forming (GHS) rats is accompanied by intestinal Ca hyperabsorptio

51 inbred genetic hypercalciuric stone-forming (GHS) rats is due, in part, to a decrease in renal tubule

52 termed genetic hypercalciuric stone-forming (GHS) rats.

53 us (QTL) mapping of rats that were bred from GHS female rats and normocalciuric Wistar Kyoto (WKY) ma

54 rat, an F2 generation of 156 rats bred from GHS female rats and normocalciuric WKY male rats was stu

55 ed in the sequence of duodenal VDR mRNA from GHS rats compared with wild-type animals.

56 is of extracts of renal cortical tissue from GHS and NC rats revealed a major 7-kb transcript of CaR

57 , different approaches to antagonize ghrelin/GHS-R1a signaling have been pursued for the treatment of

58 Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished

59 sed by pharmacological inhibition of ghrelin/GHS-R interaction.

60 indings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasivenes

61 guously demonstrated that in addition to Gq, GHS-R1a also promoted constitutive activation of G13.

62 e of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharma

63 KRd patients had higher GHS/QoL scores versus Rd patients over 18 treatment cycl

64 However, GHS-R1a is expressed in other brain regions, including t

65 Gastric hypersensitivity (GHS) contributes to epigastric pain in patients with fun

66 BACKGROUND & AIMS: Gastric hypersensitivity (GHS) contributes to epigastric pain in patients with fun

67 s show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protei

68 Conclusion KRd improves GHS/QoL without negatively affecting patient-reported sy

69 In GHS chromosome 1 congenic lines bred onto a WKY genomic

70 etermine the level of CaR gene expression in GHS rat kidney and whether CaR gene expression is regula

71 d renal CaR mRNA levels 2.0- and 3.3-fold in GHS and NC rats, respectively.

72 NC rats, CaR mRNA levels remained higher in GHS rat kidney, and the elevation was more sustained.

73 ncreased basal CaR mRNA expression levels in GHS rat kidney.

74 Under basal conditions, VDR mRNA levels in GHS rats were lower in duodenum and higher in kidney com

75 duodenal and renal calbindin mRNA levels in GHS rats, whereas they were either suppressed or unchang

76 ealed a four-fold increase in CaR protein in GHS rat renal tissue, and 1,25(OH)2D3 administration inc

77 creased VDR gene expression significantly in GHS but not normocalciuric animals, in a time- and dose-

78 In vivo half-life of VDR mRNA was similar in GHS and control rats in both duodenum and kidney, and wa

79 that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only

80 l interfering RNAs against K(v)1.1 increased GHS in naive rats.

81 ticosterone on post-natal day 15 and induced GHS in adult life.

82 y determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the abili

83 nsult to the colons of neonatal rats induced GHS in adult life.

84 nd high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to

85 ffect operates through a mechanism involving GHS-R1a.

86 The Global Health Status/Quality of Life (GHS/QoL) scale and seven subscales (fatigue, nausea and

87 Male GHS and normal control (NC) rats were fed a Ca-sufficien

88 ghrelin (AG) and UAG were abolished in male GHS-R-null mice.

89 (OH)2D3 may mediate these observations, male GHS and wild-type Sprague- Dawley normocalciuric control

90 eripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressin

91 identified as a new class of small-molecule GHS-R1a antagonists.

92 Moreover, GHS-R1a activation enhances two different paradigms of l

93 lore chemical structures that could be novel GHSs.

94 signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptor

95 ent upon acylation by GOAT and activation of GHS-R.

96 re we examined pharmacological antagonism of GHS-R in motivational incentive learning, as reflected i

97 At concentrations of GHS-R1a and SST5 expressed in islets, time-resolved FRET

98 )]-ghrelin), has enabled the distribution of GHS-R receptor protein to be directly demonstrated.

99 In this study, we examined the effect of GHS in immunological functions of 5- to 6-wk-old and 16-

100 Here we report the effects of GHS-R antagonists, some of which were potent, selective,

101 Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in stria

102 /o to Gs/olf, but only upon co-expression of GHS-R1b.

103 assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, s

104 -R1a-G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghr

105 ese results suggest dissociable functions of GHS-R in its influence over motivational learning and in

106 This hyperresponsiveness of GHS rats to 1,25(OH)2D3 (a) occurs through an increase i

107 ter neonatal insult blocked the induction of GHS in adult rats.

108 s 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes.

109 The ligation of GHS-R by ghrelin on these cells resulted in an increase

110 approaches to investigate the mechanisms of GHS in adult rats subjected to neonatal colonic insult b

111 tes that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potent

112 previously reported distribution pattern of GHS-R mRNA.

113 ly be determined from expression patterns of GHS-R mRNA or the use of immunohistochemical techniques

114 ts with GHS-R1a, but only in the presence of GHS-R1b.

115 we reveal a more complex modulatory role of GHS-R1b.

116 ate a hyperphagic response to stimulation of GHS-R in the caudal brainstem.

117 by exerting a negative allosteric effect on GHS-R1a signaling, respectively.

118 ay crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and sy

119 n, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility.

120 elin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides result

121 onstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists mig

122 ntages of responders with >/= 5- or 15-point GHS/QoL improvement at each cycle were compared between

123 ry and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.

124 e activity, we have reconstituted a purified GHS-R1a monomer in a lipid disc.

125 requirements for the interaction of purified GHS-R1a with arrestin and AP2 provide a new rationale to

126 a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a p

127 in receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant n

128 The G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretio

129 d both are mediated through ghrelin receptor GHS-R.

130 In this context, ghrelin receptor GHS-R1a is a peculiar receptor in the sense that it disp

131 of the full and functional ghrelin receptor GHS-R1a.

132 le to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique acti

133 nd inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antio

134 ptors (GPCRs), such as the ghrelin receptor (GHS-R1a), the melanocortin 3 receptor (MC(3)), and the s

135 t accommodate noncanonical ghrelin receptor (GHS-R1a)-G-protein coupling to Galpha(i/o) instead of Ga

136 ilable growth hormone secretagogue receptor (GHS-R) antagonists are reported.

137 xamide growth hormone secretagogue receptor (GHS-R) antagonists were discovered.

138 g of a growth hormone secretagogue receptor (GHS-R) from human pituitary gland and brain identified a

139 eptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ system

140 ceptor Growth Hormone Secretagogue Receptor (GHS-R), but the physiologically relevant receptor of obe

141 r, the growth hormone secretagogue receptor (GHS-R), in the caudal brainstem.

142 or the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent cir

143 or the growth hormone secretagogue receptor (GHS-R).

144 of the growth hormone secretagogue receptor (GHS-R).

145 ype 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appeti

146 ng at growth hormone secretagogue receptors (GHS-R), the only sites of action for this gastric hormon

147 5-HT(2C)-VSV isoform, significantly reduced GHS-R1a agonist-mediated calcium influx, which was compl

148 R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilita

149 modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b

150 are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential

151 stabilizes heteromer conformation, restoring GHS-R1a-Galpha(q11) coupling.

152 cDNA clone was identified encoding a second GHS-R-related gene (GPR39).

153 effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on

154 idyl small m.w. compound, a GH secretagogue (GHS), was found to induce the production of GH by the pi

155 ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the pr

156 st of the human growth hormone secretagogue (GHS) receptor.

157 relin mRNAs and growth hormone secretagogue (GHS) receptors could be detected in human oral epithelia

158 ered as a human growth hormone secretagogue (GHS).

159 Growth hormone secretagogues (GHS) are a group of synthetic peptide and nonpeptide mol

160 lecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to

161 al entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides kno

162 esized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profile

163 with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic

164 Besides, we identified some GHS-R1a ligands that preferentially activated Gq and ant

165 se differences are linked to ligand-specific GHS-R1a conformations, as assessed by intrinsic fluoresc

166 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deteriorati

167 Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and im

168 ating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling.

169 tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more comm

170 lysis was based on a Gutenberg Health Study (GHS) cohort that included 4335 eligible enrollees from a

171 Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and

172 Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiaz

173 urotrophic factor in FD-like rats suppressed GHS.

174 n (CVs) for urinary calcium (CV = 0.14) than GHS males (CV = 0.06), and the reverse in normocalciuric

175 These results demonstrate that GHS rats have high levels of CaR gene expression and CaR

176 campal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: lo

177 We have also found that GHS promoted better thymic engraftment in bone marrow tr

178 We propose that GHS-R1a activation in the hippocampus enhances excitator

179 Here we report that GHS-R and ghrelin are expressed in human T lymphocytes a

180 We show that GHS-R1a coupling to Galpha(i/o) rather than Galpha(q11)

181 Our data show that GHS-R1a is localized in the vicinity of hippocampal exci

182 The results suggest that GHS rats hyperrespond to minimal doses of 1,25(OH)2D3 by

183 nhanced in the treated mice, suggesting that GHS has a considerable immune enhancing effect, particul

184 the spleens of treated mice, suggesting that GHS may exert its immune enhancing effect by promoting c

185 This unique characteristic suggests that GHS rats may be susceptible to minimal fluctuations in s

186 eight-fold phenotypic difference between the GHS and WKY progenitors were mapped.

187 In addition, a novel heterodimer between the GHS-R1a receptor and the 5-HT(2C) receptor was identifie

188 with moderate sequence identity to both the GHS-R and neurotensin-R.

189 mosomes, distinct from the gene encoding the GHS-R and NT-R type 1.

190 xcretion was six- to eightfold higher in the GHS female than in the WKY male progenitors.

191 In the GHS group, LV fractional shortening was higher (29+/-2%)

192 oci that contribute to hypercalciuria in the GHS rat, an F2 generation of 156 rats bred from GHS fema

193 A higher proportion of KRd patients met the GHS/QoL responder definition (>/= 5-point improvement) w

194 serve the calcium excretion phenotype of the GHS parent strain.

195 recursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) ki

196 (200 nmol) intraperitoneal injections of the GHS-R antagonist GHRP-6 [D-Lys3] prior to subsequent tra

197 ential for the binding and activation of the GHS-R by structurally dissimilar GHSs, was conserved in

198 The nucleotide sequence of the GHS-R is most closely related to the neurotensin recepto

199 Superfusion of the GHS-R1A antagonists D-Lys3-GHRP-6 and JMV 3002 decreased

200 the future pharmacological targeting of the GHS-R1a receptor in the homeostatic regulation of energy

201 activity via promiscuous dimerization of the GHS-R1a receptor with other G protein-coupled receptors

202 lization following heterodimerization of the GHS-R1a receptor with the dopamine 1 receptor, as well a

203 Interestingly, dimerization of the GHS-R1a receptor with the unedited 5-HT(2C)-INI receptor

204 We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpecte

205 dopamine 1 receptor, as well as that of the GHS-R1a-MC(3) heterodimer.

206 ovel G-protein-coupled receptor (GPC-R), the GHS-R.

207 6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases

208 36 receptor with reduced affinity toward the GHS-R1a.

209 ficant amino acid sequence identity with the GHS-R and NT-Rs 1 and 2.

210 cloned and was shown to be the target of the GHSs.

211 GH release and supports the notion that the GHSs mimic an undiscovered hormone.

212 Therefore, GHS-R1b not only determines the efficacy of ghrelin-indu

213 bestatin regulates insulin secretion through GHS-R.

214 These observations ascribe to GHS a novel therapy possible for aging, AIDS, and transp

215 ry insult to the colons of rat pups leads to GHS in adult life.

216 a potential novel mechanism for fine-tuning GHS-R1a receptor-mediated activity via promiscuous dimer

217 ytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes.

218 ntake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operate

219 ocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinfla

220 duced GSIS was absent in beta-cells in which GHS-R was suppressed.

221 With GHS treatment, the ratio of LV mass to body weight incre

222 ating the different pathways associated with GHS-R1a in HEK293T cells.

223 r experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b.

224 improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a res

225 o-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and i

226 The old mice, treated with GHS for 3 wk, did not show increases in peripheral lymph

227 raised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity.

228 nd was increased from pacing CHF values with GHS treatment (55+/-7 microm/s, P:<0.05).