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

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

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

/pdf/prolactin-structure-function-and-regulation-of-secretion-3w4x6fqbg3.pdf

Prolactin: Structure, Function, and Regulation of Secretion

Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.

https://www.pnas.org/content/pnas/100/19/10972.full.pdf

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

The conformation in solution of porcine brain natriuretic peptide was determined by combined use of NMR spectroscopy and distance geometry. A set of 157 inter-proton-distance constraints was derived from the two-dimensional NOE spectra, and further a set of three hydrogen bond constraints was obtained from analysis of the temperature dependence of labile protons. The five structures with minimal violations were selected after performing distance-geometry calculations starting from 40 random initial conformations. The distance-geometry structures were further refined by the use of restrained energy minimization and restrained molecular dynamics. This structure shows a compact conformation with the carboxy-terminal region, Asn21–Tyr26, folded back to the disulfide-linked loop region, Cys4–Cys20. The characteristics of the conformation determined are as follows: conformations of the three segments interposed by glycine residues, which are Arg7–Ile12, Ser14–Leu18 and Cys20–Arg25, were well defined and the segments Arg7–Ile12 and Cys20–Arg25 are rather close to each other and nearly parallel. The biological significance of these local conformations is discussed on the basis of comparisons with those of atrial natriuretic peptide reported by Kobayashi et al. [Kobayashi, Y., Ohkubo, T., Kyogoku, Y., Koyama, S., Kobayashi, M. & Go, N. (1988) J. Biochem. (Tokyo) 104, 322–325].

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1990.tb19313.x

Conformation in solution of porcine brain natriuretic peptide determined by combined use of nuclear magnetic resonance and distance geometry.

The present invention relates to a pituitary adenylate cyclase activating polypeptide (PACAP) receptor protein or a salt thereof which is capable of binding PACAP and a method for preparing said receptor protein or salt thereof.

Method for preparing PACAP receptor protein

Human parathyroid hormone is a peptide hormone consisting of 84 amino acid residues. Production of small proteins by direct expression in Escherichia coli is often unsuccessful owing to susceptibility of the mRNA and/or the product to endogenous enzymes. In this study, direct expression of the hormone at an excellent level (over 100 mg/L) has been achieved by using a suitably designed synthetic gene under the control of the T7 promoter.



The protein produced in bacteria was extracted and easily purified in a good yield of 27 mg/L. The purified product was physico-chemically identified as intact human parathyroid hormone from the results of amino acid analysis, N-terminal sequencing, and peptide mapping using fast atom bombardment mass spectrometry. In biological assays the purified product stimulated adenylate cyclase in vitro, promoted bone growth and increased the serum osteocalcin in rats to the same extent as the authentic hormone.

Human parathyroid hormone: efficient synthesis in Escherichia coli using a synthetic gene, purification and characterization

It has been found that human renal adenocarcinoma ACHN cells synthesize and secrete immunoreactive endothelin (ir-ET) in the culture medium. Partial characterization of this material with reverse-phase high-performance liquid chromatography (RP-HPLC) suggested that ACHN cells synthesized only human endothelin-2 (ET-2). Isolation and characterization of this ir-ET-2 has revealed that this peptide has almost the same amino acid sequence and molecular weight as that of human ET-2 deduced from the nucleotide sequence of cloned human ET-2 gene

Expression of endothelin-2 (ET-2) gene in a human renal adenocarcinoma cell line: purification and cDNA cloning of ET-2.

Peptides having an amino acid sequence represented by SEQ ID NO:35 or an amino acid sequence substantially identical therewith and being capable of binding to receptor proteins having an amino acid sequence represented by SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3 or an amino acid sequence substantially identical therewith, precursors thereof or amides, esters or salts of the same. DNAs, etc. encoding the above peptides are usable in: 1) developing receptor-binding assay systems with the use of recombinant receptor protein expression systems and screening of candidates for drugs; 2) developing drugs such as memory function improving agents, appetite improving agents or function regulating agents for uterus, kidney, prostate gland, testis or skeletal muscle; etc.

Yoshihiro Ishibashi

Papers

Conformation in solution of porcine brain natriuretic peptide determined by combined use of nuclear magnetic resonance and distance geometry.

Method for preparing PACAP receptor protein

Human parathyroid hormone: efficient synthesis in Escherichia coli using a synthetic gene, purification and characterization

Expression of endothelin-2 (ET-2) gene in a human renal adenocarcinoma cell line: purification and cDNA cloning of ET-2.

Novel physiologically active peptides and utilization thereof