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PubMed1984

FMRF-amide-like immunoreactivity in brain and pituitary of the hagfish Eptatretus burgeri (Cyclostomata).

Paraffin sections of brain and pituitary of the hagfish Eptatretus burgeri were immunostained with an antiserum to FMRF-amide. Immunoreactivity was visible in a large number of neurons in the posterior part of the ventromedial hypothalamus and in long neuronal processes extending cranially from the hypothalamus to the olfactory system and caudally to the medulla oblongata. FMRF-amide-like immunoreactivity was also found in cells of the adenohypophysis. These observations suggest that the hagfish possesses a brain FMRF-amide-like transmitter system and pituitary cells containing FMRF-amide-like material. Antisera to ACTH, alpha-MSH and pancreatic polypeptide gave no immunoreaction in hagfish brain or pituitary.

Animals↗
PubMed1994

Peptidylglycine alpha-amidating monooxygenase (PAM) immunoreactivity and messenger RNA in human pituitary and increased expression in pituitary tumours.

Bioactivity of many peptides depends upon post-translational alpha-amidation of inactive precursors by two enzyme activities known collectively as peptidylglycine alpha-amidating monooxygenase (PAM). PAM enzymes are particularly abundant in the pituitary. The distribution of PAM immunoreactivity and messenger ribonucleic acid (mRNA) in the adult human pituitary and in pituitary tumours was investigated by use of immunocytochemistry and in situ hybridisation. Immunoreactivity was present in numerous cells of the anterior lobe: staining was intense in a proportion of gonadotrophs and folliculo-stellate cells, but weaker in the majority of somatotrophs and lactotrophs, a few corticotrophs and occasional thyrotrophs. PAM staining was also present in nerves, pituicytes and some endocrine cells within the posterior lobe (the human intermediate zone). Forty pituitary tumours of various types were immunoreactive for PAM; more intensely and uniformly stained than normal anterior lobe. In situ hybridisation with digoxigenin-labelled probes demonstrated intense labelling for PAM mRNA in numerous cells in normal anterior pituitary and in tumours. Many regulatory peptides that require amidation for activity, potential targets for PAM, are present in the pituitary. Many tumour growth factors also require amidation and PAM may regulate these mitogenic peptides in tumours.

Female↗
PubMed1990

Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs.

Islet amyloid polypeptide is a 37 amino acid hormone-like peptide which is the major protein component of islet amyloid deposits commonly found in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Recent studies indicate that a physiologically active form of this peptide appears to be carboxyamidated and secreted from the insulin-producing beta cell. In order to clarify the possible in vivo actions of islet amyloid polypeptide, we have studied the effects of synthesized islet amyloid polypeptide-amide on peripheral glucose utilization by performing hyperinsulinaemic euglycaemic glucose clamp studies on dogs. Exogenously administered islet amyloid polypeptide-amide (an infusion from 1.0 to 100 micrograms.kg-1.h-1, over 2 h) inhibited the insulin-stimulated glucose disposal rate in a dose dependent manner. Twenty-five micrograms.kg-1.h-1 of islet amyloid polypeptide-amide infused via a peripheral vein significantly lowered the glucose disposal rate by 20% (from 17.4 +/- 1.7 to 14.4 +/- 1.7 mg.kg-1.min-1, n = 5, p less than 0.01). These findings suggest that islet amyloid polypeptide-amide causes peripheral insulin resistance in vivo.

Amyloid↗
PubMed1994

Potent glycogenic effect of GLP-1(7-36)amide in rat skeletal muscle.

GLP-1(7-36)amide is an intestinal post-translational proglucagon product released mainly after carbohydrate ingestion, the glucose dependent insulinotropic and antidiabetogenic actions of which have been documented. In this work, by exploring whether GLP-1(7-36)amide has any effect on the glucose metabolism of the muscle, we have observed that this peptide, at physiological concentrations, exerts in this tissue an increment of the D-[U-14C]glucose incorporated into glycogen, which is accompanied by an increase in the glycogen synthase a activity; also, it stimulates both glucose oxidation and lactate formation. These data indicate that the skeletal muscle is one of the target tissues for GLP-1(7-36)amide, where its insulin-like effect explains, at least in part, its plasma glucose lowering action; thus, GLP-1(7-36)amide may well be implicated in the physiological control of glucose homeostasis after meals, not only by acting as an incretin, but also by directly promoting glucose disposal.

Animals↗
PubMed1994

Distribution of FMRF-amide-like peptide in the nervous system of a mermithid nematode, Romanomermis culicivorax.

The nervous system of the mermithid nematode Romanomermis culicivorax was investigated at different developmental stages for the distribution of the neuropeptide FMRF-amide. An FMRF-amide-like peptide was detected by an indirect immunofluorescence technique. The peptidergic nervous system increased in complexity during development. In adults, FMRF-amide-like peptide was present in the nerve ring, cephalic papillary ganglia, cephalic nerves, amphids, ganglia posterior to the nerve ring, longitudinal nerve cords and several mid-body region ganglia. The distribution of peptidergic ganglia in the tail region was different for each sex. Four clusters of ganglia were present in the tail of females, whereas such ganglia were absent in the tail of males. The results suggest that FMRF-amide-like peptide is widely distributed within the nervous system of R. culicivorax and might function as a neurohormone or neurotransmitter in controlling physiological and developmental processes.

Aedes↗
PubMedDate not supplied

Glucagon-like peptide-1(7-37) has a larger volume of distribution than glucagon-like peptide-1(7-36)amide in dogs and is degraded more quickly in vitro by dog plasma.

The pharmacokinetic properties of glucagon-like peptide-1(7-36)amide (GLP-1(7-37) were compared. Four beagle dogs received on 4 separate occasions s.c. bolus doses of 50 micrograms/kg, and 2 min i.v. infusions of 50 micrograms/kg of each peptide. The plasma immunoreactivity of GLP-1 (P-GLP-1-IR) was measured by a sandwich enzyme-linked immunosorbent assay (ELISA). After i.v. infusion, the plasma half-life in the first-phase was 2.1 +/- 0.1 and 2.4 +/- 0.3 min, in the final-phase 68 +/- 6 and 81 +/- 3 min, the total plasma clearance 25 +/- 3 and 22 +/- 4 ml/kg.min, the volume of distribution at steady state 0.16 +/- 0.02 and 0.84 +/- 0.24 l/kg, and the mean residence time 6.2 +/- 0.3 and 36 +/- 5 min for GLP-1(7-36)amide and GLP-1(7-37), respectively. After s.c. administration, the maximum plasma concentration was reached after 15 +/- 5 and 19 +/- 4 min and the absolute bioavailability was 48 +/- 7 and 49 +/- 13% for GLP-1(7-36)amide and GLP-1(7-37), respectively. P-GLP-1-IR, measured by a radioimmunoassay (RIA), was considerably higher than when measured by ELISA. This discrepancy was due to cross-reactivity with metabolites of the parent peptide. The plasma degradation was studied in vitro in dog plasma at 37 degrees C, and the half-lives were found to be 61 +/- 9 and 132 +/- 16 min for GLP-1(7-36)amide and GLP-1(7-37), respectively (n = 6). Bacitracin inhibited the degradation of both peptides.

Animals↗
PubMed1996

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Adult↗
PubMed1997

FMRF amide-like-immunoreactive primary sensory neurons in the olfactory system of the terrestrial mollusc, Limax marginatus.

The distribution of FMRF amide-like immunoreactivity was investigated in the olfactory organs in the tentacle tip of the terrestrial slug, Limax marginatus. Approximately 0.7% of the neurons in the lobules of the tentacle ganglia demonstrated FMRF amide-like immunoreactivity. Most of the FMRF amide-like-immunoreactive somata lay at superficial positions within the lobules, and dendritic processes extended to the outer surface of the sensory epithelium, whereas the axons traveled toward the cerebral ganglion through the ventral part of the tentacle nerve. From their morphological features, FMRF amide-like-immunoreactive cells were considered to be primary sensory neurons.

Animals↗
PubMed1988

Structure-activity relationships for glycine-extended peptides and the alpha-amidating enzyme derived from medullary thyroid CA-77 cells.

A peptidyl alpha-amidating enzyme has been partially purified from conditioned medium derived from cultured medullary thyroid CA-77 cells. The interactions of this enzyme with a series of tripeptides, pentapeptides, and mature glycine-extended prohormones has now been studied using a competition assay that features the enzymatic alpha-amidation of N-dansyl-Tyr-Val-Gly. While a peptide C-terminal glycine was obligatory for tight binding to the alpha-amidating enzyme, other peptide structural elements modulated the interaction. Thus, a greater than 1300-fold range in apparent inhibitor constants was observed by substitution at the -1 (penultimate) position in a C-terminal glycine-containing tripeptide with each of the 20 common L-amino acids. Peptide inhibitory potency decreased through the following amino acid groupings: sulfur containing greater than aromatic greater than or equal to histidine greater than nonpolar greater than polar greater than glycine greater than charged. This pattern was qualitatively dissimilar to that observed for a more limited series of substitutions at the -2 position, demonstrating the positional selectivity of these structural requirements. The structure-activity relationships observed with the tripeptides at the -1 position were consistent with the apparent inhibitor constants obtained for a collection of prohormones and their pentapeptide mimics. Finally, selected prohormones and their pentapeptide mimics were equipotent inhibitors, demonstrating that the peptide structural elements important for alpha-amidating enzyme recognition are located entirely within the C-terminal pentapeptide segment.

Animals↗
PubMed1986

Peptide C-terminal alpha-amidating enzyme purified to homogeneity from Xenopus laevis skin.

The C-terminal alpha-amide formation of the peptides is one of the most important events of prohormone processing. In this study, we have developed a simple and sensitive assay for monitoring alpha-amidating activity by using radioiodinated Ac-Tyr-Phe-Gly as a substrate. By utilizing this assay, an alpha-amidating enzyme was first purified to homogeneity from Xenopus laevis skin. The purified enzyme has a single polypeptide chain with an apparent molecular weight of 39,000 and its N-terminal sequence was determined as Ser-Leu-Ser-. The enzyme converts several synthetic peptides with C-terminal glycine to the corresponding des-glycine peptide alpha-amides. The enzyme activity, with an optimal pH 6-7, was dependent on the copper ion and ascorbate. In the presence of 0.25 mM ascorbate, the enzyme exhibited a Km of 0.35 microM and a Vmax of 1.9 nmol/microgram/h for Ac-Tyr-Phe-Gly.

Amino Acid Sequence↗
PubMed1988

Cloning of cDNA encoding a new peptide C-terminal alpha-amidating enzyme having a putative membrane-spanning domain from Xenopus laevis skin.

A cDNA clone encoding a precursor of a peptide C-terminal alpha-amidating enzyme (AE-I) from Xenopus laevis skin was recently isolated and sequenced in our laboratory. In this study, by using the restriction fragment of this clone as a hybridization probe, we have identified the cDNA encoding another new peptide C-terminal alpha-amidating enzyme (tentatively named AE-II) distinct from AE-I. The cDNA encodes a polypeptide of 875 amino acid residues, which contains a region extensively homologous to AE-I precursor at N-terminus. The encoded protein characteristically has a putative membrane-spanning domain near C-terminus. Our results indicate that C-terminal alpha-amide formation of peptides in Xenopus skin is regulated by at least two distinct alpha-amidating enzymes.

Amino Acid Sequence↗
PubMed1992

Peptide amidating enzymes are present in cultured endothelial cells.

Carboxy-terminal amidation is a prevalent post-translational modification necessary for the bioactivity of many peptides. We now report that the two enzymes essential for amidation, peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase (PGL), are present in both the cytosol and membrane fractions of cultured bovine aortic endothelial cells. Endothelial PAM exhibits ascorbate-dependent turnover and is inactivated by the mechanism-based inactivator, 4-phenyl-3-butenoic acid (PBA), whereas PGL activity is independent of ascorbate and is not affected by PBA. These enzymological characteristics correspond to those of amidating enzymes from other tissues. These results suggest a heretofore unrecognized role for alpha-amidated peptides in cardiovascular function.

Amidine-Lyases↗
PubMed1982

Determination of [amide-15N]glutamine in plasma with gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method is described for determination of isotopic enrichment in [amide-15N]glutamine. The method involves the isolation of glutamine with an anionic exchange resin and the enzymatic hydrolysis of glutamine with glutaminase. The ammonia derived from the amide group is converted enzymatically to glutamic acid and isotopic enrichment in the latter compound is determined following formation of the N-TFA-glutaminate derivative. The method gave a linear result for [amide-15N]glutamine in the 0.5--21.5 atom % excess range with a mean coefficient of variance of 7.8%. Determination of plasma glutamine by isotope dilution showed a mean recovery of 94%. The appearance of plasma [amide-15N]glutamine was measured in a healthy adult following the intravenous administration of 15NH4Cl (350 mumol). A peak enrichment of 12 atom % excess was observed by 3.5 min.

Ammonia↗
PubMed1990

The importance of the C-terminal amide structure of rat pancreastatin to inhibit pancreatic exocrine secretion.

A C-terminal fragment of rat pancreatatin, a 26 residue peptide amide and a fragment without a C-terminal amide were synthesized by Fmoc-based solid phase methods and their biological activities were compared. The rat C-terminal fragment inhibited pancreatic exocrine secretions produced by the intravenous injection of 2-deoxy-D-glucose (a central vagal nerve stimulation), whereas the fragment without a C-terminal amide showed no effect on pancreas. These results indicate that the C-terminal amide of this peptide is necessary to reveal its biological activity.

Animals↗
PubMed1991

Characterization of glucagon-like peptide-I(7-36)amide receptors of rat lung membranes by covalent cross-linking.

125I-labelled GLP-I(7-36)amide was cross-liked to a specific binding protein in rat lung membranes using disuccinimidyl suberate. A single radio-labelled band at Mr 66,000 was identified by SDS-PAGE after solubilization of the ligand-binding protein complex which is consistent with the presence of a single class of binding sites on rat lung membranes. The band was undetectable when 1 mumol/l GLP-I(7-36)amide was included in the binding assay. No change in the mobility of the band was observed under reducing conditions suggesting that the binding protein in the receptor is not part of a larger disulphide-linked protein. The intensity of the radiolabelled protein band was reduced when the incubation with 125I-labelled GLP-I(7-36)amide was carried out in the presence of guanine nucleotides suggesting that the GLP-I(7-36)amide receptor is coupled to the adenylate cyclase system.

Animals↗
PubMed1987

Peptidyl-glycine alpha-amidating monooxygenase is present in islet secretory granules of the anglerfish, Lophius americanus.

Anglerfish islet secretory granules have been examined for the presence of an enzyme which could perform C-terminal amidation of glucagon-like peptide II and possibly anglerfish peptide Y. Using [125I]D-Tyr-Val-Gly as substrate, a peptidyl-glycine alpha-amidating monooxygenase (PAM) was detected in islet secretory granule lysates. The enzyme is active between pH 6.0 and 8.5 and exhibits maximal activity near pH 7.0. The islet PAM requires Cu2+, ascorbate, and molecular oxygen for activity. Other divalent metal ions and redox cofactors were tested and found to be inactive in the assay. Even though added Cu2+ and ascorbate are required for detecting islet PAM activity, when these factors were incubated with substrate in the absence of secretory granule lysate, no activity was observed. It was also found that the addition of higher than optimal concentrations of either Cu2+ or ascorbate inhibited amidating activity. The results demonstrate that a PAM is present in secretory granules of anglerfish islet tissue. The characteristics of the islet PAM are similar to those of PAMs identified and characterized in other tissues which produce bioactive C-terminally amidated peptides.

Animals↗
PubMed1991

Kinetic analyses of peptidylglycine alpha-amidating monooxygenase from pancreatic islets.

Peptidylglycine alpha-amidating monooxygenase (PAM) plays an important role in the post-translational processing of bioactive neuropeptides by participating in C-terminal amidation. We have examined PAM activity in the pancreatic islets of the anglerfish (AF), Lophius americanus. It was previously demonstrated that the cofactor requirements and pH optimum for the fish PAM are essentially identical to PAM obtained from other tissues and species. The present study was performed to examine the enzymatic characteristics of the fish islet PAM in more detail. One of the questions addressed was the suitability of the AF islet neuropeptide Y-like peptide, aPY-Gly, as a substrate for the islet PAM. Partially purified PAM from AF islet secretory granules was incubated with [125I] aPY-Gly and the resulting products were analyzed by HPLC. The islet PAM readily mediated the formation of aPY-amide from aPY-Gly. PAM purified from bovine adrenal chromaffin granules also catalyzed the amidation of [125I] aPY-Gly. The kinetic parameters of the islet PAM were examined using trinitrophenylated-D-Tyr-Val-Gly (TNP-D-YVG) and 4-nitrohippuric acid (4-NHA). The Km of the islet PAM was 25 +/- 5 microM for TNP-D-YVG and 3.4 +/- 1 mM for 4-NHA. The competitive inhibitor of mammalian PAM activity, 4-methoxybenzoxyacetic acid, proved to be a potent inhibitor of the islet PAM as well, with an apparent KI of 0.06 mM. These results demonstrate that the AF islet PAM exhibits substrate compatibility, kinetic parameters, and inhibitor susceptibility quite similar to the characteristics of PAM from other tissues and species.

Adrenal Medulla↗
PubMed1993

Amylin alters the biological action of the incretin hormone GLP-1(7-36)amide.

We investigated the effect of amylin on the glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) induced stimulation of cAMP production in RINm5F cells. Amylin and the structurally related calcitonin gene-related peptide (CGRP) inhibited the stimulatory effect of GLP-1(7-36)amide on cAMP generation while substance P was without effect. Amylin had no effect on the forskolin-induced cAMP-generation. These findings suggest that amylin alters the biological action of the incretin hormone GLP-1(7-36)amide. This could at least partly contribute to an amylin-induced impaired glucose tolerance which has been previously observed.

Adenylyl Cyclases↗