Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it "ghrelin," after a word root ("ghre") in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2004

Ghrelin: Structure and Function

The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

The Calpain System

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Context Epidemiological studies have indicated an inverse association between cardiorespiratory fitness (CRF) and coronary heart disease (CHD) or all-cause mortality in healthy participants. Objective To define quantitative relationships between CRF and CHD events, cardiovascular disease (CVD) events, or all-cause mortality in healthy men and women. Data Sources and Study Selection A systematic literature search was conducted for observational cohort studies using MEDLINE (1966 to December 31, 2008) and EMBASE (1980 to December 31, 2008). The Medical Subject Headings search terms used included exercise tolerance, exercise test, exercise/physiology, physical fitness, oxygen consumption, cardiovascular diseases, myocardial ischemia, mortality, mortalities, death, fatality, fatal, incidence, or morbidity. Studies reporting associations of baseline CRF with CHD events, CVD events, or all-cause mortality in healthy participants were included. Data Extraction Two authors independently extracted relevant data. CRF was estimated as maximal aerobic capacity (MAC) expressed in metabolic equivalent (MET) units. Participants were categorized as low CRF ( Data Synthesis Data were obtained from 33 eligible studies (all-cause mortality, 102 980 participants and 6910 cases; CHD/CVD, 84 323 participants and 4485 cases). Pooled RRs of all-cause mortality and CHD/CVD events per 1-MET higher level of MAC (corresponding to 1-km/h higher running/jogging speed) were 0.87 (95% confidence interval [CI], 0.84-0.90) and 0.85 (95% CI, 0.82-0.88), respectively. Compared with participants with high CRF, those with low CRF had an RR for all-cause mortality of 1.70 (95% CI, 1.51-1.92; P  Conclusions Better CRF was associated with lower risk of all-cause mortality and CHD/CVD. Participants with a MAC of 7.9 METs or more had substantially lower rates of all-cause mortality and CHD/CVD events compared with those with a MAC of less 7.9 METs.

https://jamanetwork.com/journals/jama/articlepdf/1108396/jcr90003_2024_2035.pdf

Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women: A Meta-analysis

Background Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. Methods We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein–coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. Results Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotro...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa035322

The GPR54 gene as a regulator of puberty

Identification of Neuromedin U Receptors

LIGHT (TNFSF14, CD258) is a member of the tumor necrosis factor (TNF) ligand superfamily, which is involved in innate and adaptive immune responses as well as in regulation of cell survival and proliferation. LIGHT forms a membrane-anchored homotrimeric complex on the cell surface and is often processed as a soluble protein. In this study, we established an effective strategy for producing bioactive soluble forms of human LIGHT (s-hLIGHT), which is an extracellular region (Ile(84)-Val(240)) of human LIGHT (hLIGHT), and soluble forms of mouse LIGHT (s-mLIGHT), which is an extracellular region (Asp(72)-Val(239)) of mouse LIGHT (mLIGHT). To enhance the refolding of s-hLIGHT from inclusion bodies in Escherichia coli, we added L-cysteine to the denaturation buffer, which significantly improved the refolding efficiency of s-hLIGHT. However, there was little information available about the biological activity of mLIGHT in the literature because of the difficulty in producing bioactive s-mLIGHT. We produced trimeric s-mLIGHT by fusing s-mLIGHT with a trimerization domain termed "foldon" from bacteriophage T4 fibritin (Foldon-mLIGHT). We further demonstrated that Foldon-mLIGHT inhibited the growth of mouse carcinoma cells at the picomolar range, indicating that trimerization of s-mLIGHT is essential for its biological activity.

Effective expression and purification of bioactive recombinant soluble LIGHT.

PROBLEM TO BE SOLVED: To obtain a new G-protein conjugated receptor protein consisting of a G-protein conjugated receptor protein (salt) containing a specific amino acid sequence which is useful for screening the agonist/antagonist, the prophylaxis or treatment of diseases associated with functional failures of the protein, or the like SOLUTION: A new G-protein conjugated receptor protein (salt) containing an amino acid sequence identical or substantially identical to the amino acid sequence expressed by the formula The protein (salt) is useful for screening the agonist/antagonist, the prophylaxis and/or treatment of diseases associated with functional failures of the G-protein conjugated receptor protein This protein is obtained by cloning through PCR reaction using a cDNA of human fetal brain as a template and a primer consisting of a partial sequence of a gene encoding the G-protein conjugated receptor protein; integrating the obtained gene into a vector to prepare a recombinant vector; transducing the recombinant vector into a host cell to transform the cell; and subsequently culturing the transformant

New g-protein conjugated receptor protein and dna of the protein

A compound that promotes the ubiquitination of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence shown by SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3 or a partial peptide thereof or a salt thereof, or a salt thereof, a compound that promotes the degradation, by proteasome, of the protein or a partial peptide thereof or a salt thereof, or a salt thereof, and the like can be used as, for example, prophylactic/therapeutic agents for neurodegenerative disease. Also, a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence shown by SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3 or a partial peptide thereof or a salt thereof and the like are useful for screening for a compound having prophylactic/therapeutic action on neurodegenerative disease and the like or a salt thereof.

Screening method for an agent for treatment of neurodegenerative disease

L'invention concerne des proteines receptrices couplees aux proteines G tirees du voisinage du tronc cerebral du rat et du cerveau humain, ou leurs sels, leurs fragments peptidiques ou leurs amides, esters ou sels, leurs ligands, une methode/un kit de criblage de composes capable de modifier les proprietes de liaison des ligands aux proteines receptrices couplees aux proteines G, leurs composes ou sels obtenus par le criblage precite, des anticorps contre les proteines receptrices couplees aux proteines G, etc.

Yasushi Shintani

Papers

Identification of Neuromedin U Receptors

Effective expression and purification of bioactive recombinant soluble LIGHT.

New g-protein conjugated receptor protein and dna of the protein

Screening method for an agent for treatment of neurodegenerative disease

NOUVELLES PROTEINES RECEPTRICES COUPLEES AUX PROTEINES G, LEURS ADN ET LEURS lIGANDS