MEASUREMENT OF γ-AMINOBUTYRIC ACID IN ISOLATED NERVE CELLS OF CAT CENTRAL NERVOUS SYSTEM

Abstract— A sensitive method for measuring γ-aminobutyric acid (GABA) has been developed. This method consists of a combination of the enzymic GABA assay of J akoby and S cott (1959) with the enzymic cycling technique of L owry , P assonneau , S chulz and R ock (1961) and permits the measurement of as little as 2 × 10⁻¹⁴ mol of GABA. Using this method, GABA analyses were made on single isolated nerve cell bodies of different types from the CNS of the cat. Average GABA concentrations in these cell bodies were: spinal ganglion cells, 0.2 m m ; spinal mononeurons, 0.9 m m ; large cells of the ventral part of Deiters' nucleus, 2.7 m m ; large cells of the dorsal part of Deiters' nucleus, 6.3 m m ; cerebellar nuclei cells, 6.0 m m ; cerebellar Purkinje cells, 6.6mM; cerebral Betz cells, 2.5 m m .
The GABA concentrations in the isolated dorsal Deiters' cells were greatly reduced (1.7 m m ) after the removal of the cerebellar vermis while those of the ventral Deiters' cells were unaffected by the denervation. These results suggest that GABA is concentrated within axon terminals, probably of Purkinje neurons, synapsing with the dorsal Deiters' cells. The results of GABA analyses on isolated nerve cells are discussed in relation to the relevant neuronal functions and the possible role of GABA as an inhibitory transmitter.     

Activation of phosphorylase kinase from brain by small amounts of calcium ion

E lectrical stimulation of brain results in an enhancement of glycogen breakdown (K ing , L owry , P assonneau and V enson , 1967) and one should therefore expect exitation to be linked in some way to glycogen metabolism. Stimulation of muscle cells, which induces contraction, also increases glycogen breakdown. In this case it has been shown that a minute amount of Ca²⁺, which couples excitation and contraction, also serves as a link between excitation and glycogenolysis (O zawa , H osoi and E bashi , 1967). A small amount of Ca²⁺, released into the sarcoplasm as a result of excitation of the cell membrane, activates phosphorylase kinase. The activated kinase, in turn, converts phosphorylase α (the inactive form of phosphorylase) to phosphorylasea (the active form). The present communication summarizes the evidence that a similar mechanism operates in brain.     

Increase of brain tryptophan and stimulation of serotonin synthesis by salicylate

I ndirect evidence indicates that the rate-limiting step in the synthesis of brain 5-HT is the concentration of tryptophan in brain and not, as previously considered (G reen and S awyer , 1966), tryptophan hydroxylase. In fact this enzyme has a K_m for its substrate much higher than the concentration of tryptophan normally present in the mammalian brain (J equier , L ovenberg and S joerdsma , 1967; J equier , R obinson , L ovesberg and S joerdsma , 1969; M cgeer , P eters and M cgeer , 1968). Tryptophan is the only amino acid circulating in plasma which is highly bound to serum proteins (M cmenamy and O ncley , 1958). We have previously shown that the free fraction of serum tryptophan controls the concentration of brain tryptophan and, therefore, 5-HT synthesis as well (T agliamonte , B iggio and G essa , 1971d; G essa , B iggio and T agliamonte , 1972). Salicylate has been shown to displace tryptophan from its protein binding in plasma and to raise the free tryptophan concentration (M carthur and D awkins , 1969; S mith and L akatos , 1971). These considerations prompted us to study the effect of salicylate on tryptophan concentrations and 5-HT metabolism in brain.     

Isolation of glycosaminoglycans and variation with age in the feline brain

M any laboratories have reported the presence of glycosaminoglycans (GAG) in the brains of a variety of species, including monkey, man, cat, pig, rabbit, sheep, rat and chicken (C handrasekaran and B achhawat , 1969; C lausen and H ansen , 1963; C lausen and R osenkast , 1962; C ustod and Y oung , 1968; M argolis , 1967; O nodera , H irona , H oriuchi and K ashimura , 1966; S aigo and E gami , 1970; S ingh and B achhawat , 1965 , 1968; S ingh , C handrasekaran , C herian and B achhawat , 1969). Because of the interest of our laboratory in the GAG of the cat brain (C ustod and Y oung , 1968; Y oung , 1963), we initiated the present studies to quantify these various brain polysaccharides and to investigate their changes as a function of postnatal age.     

Relationships between shoot to root ratio, growth and leaf soluble protein concentration of Pisum sativum, Phaseolus vulgaris and Triticum aestivum under different nutrient deficiencies

Relations between shoot to root dry weight ratio (S : R), total plant dry weight (DW), shoot and plant N concentration and leaf soluble protein concentration were examined for pea ( Pisum sativum L.), common bean ( Phaseolus vulgaris L.) and wheat ( Triticum aestivum L.) under different nutrient deficiencies. A regression model incorporating leaf soluble protein concentration and plant DW could explain greater than 80% of the variation in S : R within and between treatments for pea supplied different concentrations of NO₃^– or NH₄⁺ in solid substrate; pea and bean supplied different concentrations of N, P, K and Mg in liquid culture; and wheat supplied different concentrations of N, P, K, Mg, Ca and S in liquid culture. Addition of shoot or plant N concentration to the model explained little more of the variation in S : R. It is concluded that results are consistent with the proposal that macronutrient effects on S : R are primarily mediated through their effects on protein synthesis and growth.     

Besprechungen

Book reviewed in this article: Alexander , B. K., und E. M. Roth (1971): The effects of acute crowding on aggressive behavior of Japanese Monkeys Brown , Jerram L. (1971): An exploratory study of vocalization areas in the brain of the Red winged Blackbird Hogan , Jerry A. (1971): The development of a hunger system in young chicks Castell , Rolf, und Carolyn Wilson (1971): Influence of spatial environment on development of mother-infant interaction in Pigtail Monkeys Yadava , R. P. S., und M. V. Smith (1971): Aggressive behaviour of Apis mellifera L. workers towards introduced queens Kovach , Joseph K. (1971): Ethology in the Soviet Union Wiepkema , P. R. (1971): Positive feedbacks at work during feeding Hafez , Mahmud, H. S. Salama und R. A. Tolba (1971): Reactions of the corn borer Schmidt , Robert S. (1971): A model of the central mechanisms of male Anuran acoustic behavior Davenport , R. K. und G. M. Rogers (1971): Perception of fotografs by apes ed. Carthy , J. D., und G. E. Newell (1968): Invertebrate receptors Rensch , Bernhard (1971): Probleme der Gedächtnisspuren Tinbergen , N. (1971): Clever gulls and dumb ethologists — or: the trackers tracked De Lannoy , J., und M. Wielerrians (1969): Le schéma du jeune congénère Gray , Annie P. (1971): Mammalian hybrids, a check-list with bibliography     

Besprechungen

Book Reviewed in this article: Spencer, Booth Y., und R. A. Hinde (1969): Tests of behavioral characteristics for Rhesus Monkeys (Tests für Verhaltensunterschiede bei Rhesusaffen). Vaidya, Viduadhar G. (1969): Form perception in Papilio demoleus L. (Formwahrnehmung bei P. d.). Rabinowitch, Viktor (1969): The role of experience in the development and retention of seed preferences in Zebra finches (Anteil der Erfahrung an der Futterwahl von Zebrafinken). Emlen, John T. , und Don E. Miller (1969): Pace-setting mechanisms of the nesting cycle in the ring-billed Gull (Über Mechanismen, die das Zeitmaß einzelner Phasen des Fortpflanzungszyklus von Larus delawarensis beeinflussen). Eisner, Erica (1969): The effect of hormone treatment upon the duration of incubation in the Bengalese Finch (Beeinflußbarkeit der Brutzeit des japanischen Mövchens). Marr, John N., und Lawrence G. Lilliston (1969): Social attachment in Rats by odor and age (Verhalten von Ratten zu Artgenossen abhängig von ihrem Geruch und Alter). Smith, W. J. (1969): Displays of Sayornis phoebe (Soziale Verständigungsweisen des Tyranniden S. p.). Denenberg, Victor H., Rhoda E. Taylor und M. X. Zarrow (1969): Maternal behaviour in the Rat; an investigation and quantification of nest building (Verhalten von Rattenmüttern: eine quantitative Untersuchung des Nestbauens). Abu Gideiri, Y. B. (1969): The development of behaviour in Tilapia nilotica L. (Die Verhaltensentwicklung bei T. n.). Stout, John F., Carl R. Wilcox und Lynn E. Creitz (1969): Aggressive communication by Larus glaucescens Part 1. Sound communication (Angriffsverhalten der Beringmöwe I. Laute). Stout, John F. , und Melvin E. Brass (1969): Aggressive communication by Larus glaucescens II. Visual communication (Angriffsverhalten der Beringmöwe. Visuelle Auslöser). Norton-Griffiths, M. (1969): Organisation, control, and development of parental feeding in the Oyster Catcher (Haematopus ostralegus) (Aufbau, Kontrolle und Entwicklung des Jungefütterns beim Austernfischer). Alexander, S. J. , und D. W. Ewer (1969): A comparative study of some aspects of the biology and ecology of Sesarma catenata Ort. and Cyclograpsus punctatus M. Eds., with additional observations on Sesarma meinerti De Man. (Vergleichend biologische und ökologische Untersuchungen an Krabben der Gattungen Sesarma und Cyclograpsus). Thinès, G. (1969): L'évolution régressive des poissons cavernicoles et abyssaux (Rudimentationen in der Evolution der Höhlen- und Tiefseefische). Milliard, N. A. H. (1966): Contributions to the functional morphology of fishes (Beiträge zur funktionellen Morphologie der Fische). I. Introduction. Field, J. G. (1966): Dasselbe II. The feeding mechanism of the angler-fish, Lophius piscatorius Linn (Die Freßweise des Anglerfisches). Branch, G. M. (1966): Dasselbe III. The feeding mechanism of Syngnathus acus Linn (Die Freßweise der Seenadel Syngnathus). Lamoral, B. H. , und N. A. H. Milliard (1967): Dasselbe IV. The locking mechanism of the dorsal spine of the catfish Synodontis zambesensis Peters (Die Arretierung des Rückenstachels beim Wels Synodontis). Vrba, E. S. (1968): Dasselbe V. The feeding mechanism of Elops saurus L. (Die Freßweise des “Tarpuns” Elops). Visser, J. (1966): Colour change in Leptotyphlops scutifrons (Peters) and notes on its defensive behaviour (Farbwechsel und Sich-Totstellen bei einer Schlankblindschlange). Brosset, A. (1969): La vie sociale des oiseaux dans une forêt équatoriale du Gabon (Das Zusammenleben der Vögel in einem Åquatorwald in Gabun). Rahm, U. (1969): Dokumente über Anomalurus und Idiurus des östlichen Kongo. Walther, Fritz (1968): Verhalten der Gazellen. Thorpe, W. H. (1969): Der Mensch in der Evolution, Naturwissenschaft und Religion. Übersetzt von Edith Zerbin-Rüdin. Bunak, V. V. (1968): Die Entwicklungsstadien des Denkens und des Sprachvermögens und die Wege ihrer Erforschung. Count, E. W. (1968): An essay on Phasia, on the Phylogenesis of Man's Speech Function (Ein Essay über Sprachfähigkeit und Stammesgeschichte der menschlichen Sprachleistung). Löbsack, Th. (1968): Die Biologie und der liebe Gott, Aspekte einer zukunftsreichen Wissenschaft. Sury, K. v. (1967): Wörterbuch der Psychologie und ihrer Grenzgebiete, 3. Aufl. Vogel, G. , und H. Angermann (1967 und 1968): dtv-Atlas zur Biologie, Tafeln und Texte.     

Eine Methode zur Prüufung innertherapeutisch wirkender Fungizide

Abstract

Burnett, J. H.: Fundamentals of Mycology. Edward Arnold, London, 1968. 546 S., 175 Abb., 96 Tab., 9 Taf., geb., £ 6 10 s. Reviewed by W. Kühnel.

Smith, R. F. (Ed.): Annual Review of Entomology. Vol. 14, Annual Reviews Inc., Palo Alto, 1969, 478 S., 6 Abb., 25 Tab., 6 Tafeln, geb. $ 9.00. Reviewed by R. Fritzsche.

Somogyi, J. C.; Francois, A. C.: Antibioties in Agriculture. Basel, S. Karger AG, 1968, 208 S., 28 Abb., 50 Tab., brosch., sF/DM 57,—. Reviewed by H. J. Müller.

Metlitskh, B. L.; Ozeretskovskaya, O. L.: Plant immunity: Biochemical aspects of plant resistance to parasitic fungi. Plenum Press, Now York, 1968, 114 S., 9 Abb., 18 Tab., geb., 12,50 $. Reviewed by H. Wolffgang.     

Book reviews

THE BIOLOGY OF MOSSES. by D. H. S. R ichardson
PRINCIPLES OF GENETIC MANIPULATION: AN INTRODUCTION TO GENETIC ENGINEERING . By R. W. O ld & S. B. P rimrose Second Edition
HANDBOOK OF PLANT VIRUS INFECTIONS: COMPARATIVE DIAGNOSIS . Edited by E douard K urstak .
CYTOGENETICS . By J urgen S chulz -S chaeffer
PLANT SCIENCE: AN INTRODUCTION TO WORLD CROPS . By J. J anick , R. W. S chery , F. W. W oods , & V. W. R uttan     

The Random Phenotype Concept, with Applications

A random phenotype is defined as a probability distribution over any given set of phenotypes. This includes as special cases the kinds of phenotypes usually considered (qualitative, quantitative, and threshold characters) and all others. Correspondingly general methods are indicated for analyzing data of all forms in terms of the classical Mendelian factor concept (as distinct from the biometrical methods usually applied to measurement and graded data, associated with the effective factor concept). These are applied in a new analysis of the data of E. L. Green (1951, 1954, 1962) on skeletal variation in the mouse. The adequacies of various classical one-factor and several-factor models are considered. Indications of an underlying scale are found from this new standpoint. The results are compared with those obtained by Green using the scaling approach. An illustrative application is also made to some of Bruell's (1962) continuous behavioural data on mice. This work was substantially completed in 1959 but not previously prepared for publication. The same approach was originated and developed independently by R. L. Collins who has treated a wider range of theoretical problems (cf. Collins 1967, 1968a, 1969b, 1970c) and a wider range of applications (cf. Collins and Fuller 1968; Collins 1968b, 1969a, 1970a). A less general independent development is that of Mode and Gasser 1972.     

The complete amino acid sequence of coagulogen isolated from Southeast Asian horseshoe crab, Carcinoscorpius rotundicauda

The complete amino acid sequence of coagulogen purified from the hemocytes of the horseshoe crab Carcinoscorpius rotundicauda was determined by characterization of the NH2-terminal sequence and the peptides generated after digestion of the protein with lysyl endopeptidase, Staphylococcal aureus protease V8 and trypsin. Upon sequencing the peptides by the automated Edman method, the following sequence was obtained: A D T N A P L C L C D E P G I L G R N Q L V T P E V K E K I E K A V E A V A E E S G V S G R G F S L F S H H P V F R E C G K Y E C R T V R P E H T R C Y N F P P F V H F T S E C P V S T R D C E P V F G Y T V A G E F R V I V Q A P R A G F R Q C V W Q H K C R Y G S N N C G F S G R C T Q Q R S V V R L V T Y N L E K D G F L C E S F R T C C G C P C R N Y Carcinoscorpius coagulogen consists of a single polypeptide chain with a total of 175 amino acid residues and a calculated molecular weight of 19,675. The secondary structure calculated by the method of Chou and Fasman reveals the presence of an alpha-helix region in the peptide C segment (residue Nos. 19 to 46), which is released during the proteolytic conversion of coagulogen to coagulin gel. The beta-sheet structure and the 16 half-cystines found in the molecule appear to yield a compact protein stable to acid and heat. The amino acid sequences of coagulogen of four species of limulus have been compared and the interspecies evolutionary differences are discussed.     

Levels of brain lipids in white matter from undernourished Sinclair (S-1) miniature swine

I t H as been suggested previously that animal models are the preferred method for biochemical study concerned with protein-calorie malnutrition (K irsch , S aunders and B rock , 1968; D obbing , 1970). That the brain is one of the least vulnerable organs to be affected by dietary deprivation has been reported for swine (P latt , H eard and S tewart , 1964; T umbleson , T insley , C orwin , F latt and F lynn , 1969; T umbleson , T insley , M ulder and F lait , 1970), rhesus monkeys (O rdy , S amorajski and H ershberger , 1970) and rats (B rown and G uthrie , 1968). However, alteration of brain composition as a result of protein-calorie malnutrition at a young age may have important effects on the mental and behavioural activities of the maturing subjects (W inick , 1970; C ravioto , 1970). In a previous study on the effect of undernutrition in young miniature swine, it was noted that there was an elevation in the levels of cholesterol and glucose in serum of pigs fed the low protein diet (T umbleson et al. , 1969). The duration of such elevations was usually 2–8 weeks after administration of the test diet. Since cholesterol, as well as other chemical constituents, in serum is important for the biosynthesis of brain membranes, the present study was designed to assess the effect of undernutrition on levels of major brain lipids.     

A perforated patch-clamp study of calcium currents and exocytosis in chromaffin cells of wild-type and alpha(1A) knockout mice

Simultaneous recordings of inward whole-cell Ca(2+) channel currents (I(Ca) ) and increments of capacitance as an indication of exocytosis (Delta(Cm)), were performed in voltage-clamped single adrenal chromaffin cells from wild-type and alpha(1A) subunit deficient mice, using the perforated-patch configuration of the patch-clamp technique. Using protocol #1 (one single Ca(2+) channel blocker per cell), to dissect the components of I(Ca), L channels contributed 43%, N channels 35% and P/Q channels 30% to the total I(Ca) of wild-type cells. Using protocol #2 (cumulative sequential addition of 3 microm nifedipine, 1 microm omega-conotoxin GVIA, and 1 microm omega-agatoxin IVA), L, N and P/Q channels contributed 40%, 34% and 14%, respectively, to I(Ca); an R component of around 11% remained. In wild-type mice the changes of Delta(Cm) paralleled those of I(Ca). In alpha(1A) deficient mice the L component of I(Ca) rose to 53% while the P/Q disappeared; the N and R components were similar. In these mice, Delta(Cm) associated to N and R channels did not vary; however, the P/Q component was abolished while the L component increased by 20%. In conclusion, exocytosis was proportional to the relative density of each Ca(2+) channel subtype, L, N, P/Q, R. Ablation of the alpha(1A) gene led to a loss of P/Q channel current and to a compensatory increase of L channel-associated secretion; however, this compensation was not sufficient to maintain the overall exocytotic response, that was diminished by 35% in alpha(1A) -deficient mice. This may be due to altered Ca(2+) homeostasis in these mice, as compared to wild mouse chromaffin cells.     

REVIEWS

Pflanzliche Infektionslehre. By E rnst G äumann
Marine Microbiology. A Monograph on Hydrohacteriology. By Prof. C laude E. Z obell .
An Introduction to the Taxonomy and Nomenclature of Fungi. By G. R. B isby
pH and Plants. An introduction for beginners. By J ames S mall , D.SC.
Laboratory Manual of Elementary Botany. By A rthur W. H aupt , Ph.D.
American Species of Amelanchier. By G. N. J ones .
Luther Biirbank. A Victim of Hero Worship. By W alter L. H oward , Ph.D.
Trace Elements in Plants and Animals. By W. S tiles .
An Introduction to B0Iany. By A rthur W. H aupt .
Crop Production and Environment. By R. O. W hyte .
Principles of Agricultural Botany. By A lexander N elson .     

Thermodynamic substantiation of water-bridged collagen structure.

A solution of the problem of topology of a hydrogen bond net in a triple helix of collagen is suggested on the basis of an analysis of thermodynamic data on denaturation of phylogenetically different collagen [T. V. Burjanadze (1982), Vol. 21, pp. 1489-1501; T. V. Burjanadze, E. I. Tiktopulo, and P. L. Privalov (1987), Dokl. Akad. Nauk. USSR, Vol. 293, pp. 720-724] as well as on the earlier evaluation of the energy of the OH group of the 4-hydroxyproline bond [A. R. Ward and P. Mason (1973), Journal of Molecular Biology, Vol. 29, pp. 431-435]. It is shown that only the water-bridged collagen structure [G. N. Ramachandran and R. Chandrasekharan (1968), Biopolymers, Vol. 6, pp. 1649-1661; G. N. Ramachandran, M. Bansal, and R. S. Bhatnagar (1973), Biochimica Biophysica Acta, Vol. 322, pp. 166-171; M. Bansal, C. Ramakrishnan, and G. N. Ramachandran (1975), Proceedings of the Indian Academy of Sciences, Vol. 82, pp. 152-164] can explain both the change of thermostability upon proline hydroxylation [J. Rosenbloom, M. Harsch, and S. Jimenez (1973), Archives of Biochemistry and Biophysics, Vol. 158, pp. 478-484] and its phylogenetic change [T. V. Burjanadze (1982)].     

The complete amino acid sequence of the low molecular weight cytosolic acid phosphatase

This paper presents the complete amino acid sequence of the low molecular weight acid phosphatase from bovine liver. This isoenzyme of the acid phosphatase family is located in the cytosol, is not inhibited by L-(+)-tartrate and fluoride ions, but is inhibited by sulfhydryl reagents. The enzyme consists of 157 amino acid residues, has an acetylated NH2 terminus, and has arginine as the COOH-terminal residue. All 8 half-cystine residues are in the free thiol form. The molecular weight calculated from the sequence is 17,953. The sequence was determined by characterizing the peptides purified by reverse-phase high performance liquid chromatography from tryptic, thermolytic, peptic, Staphylococcus aureus protease, and chymotryptic digests of the carboxymethylated protein. No sequence homologies were found with the two known acylphosphatase isoenzymes or the metalloproteins porcine uteroferrin and purple acid phosphatase from bovine spleen (both of which have acid phosphatase activity). Two half-cystines at or near the active site were identified through the reaction of the enzyme with [14C] iodoacetate in the presence or in the absence of a competitive inhibitor (i.e. inorganic phosphate). Ac-A E Q V T K S V L F V C L G N I C R S P I A E A V F R K L V T D Q N I S D N W V I D S G A V S D W N V G R S P N P R A V S C L R N H G I N T A H K A R Q V T K E D F V T F D Y I L C M D E S N L R D L N R K S N Q V K N C R A K I E L L G S Y D P Q K Q L I I E D P Y Y G N D A D F E T V Y Q Q C V R C C R A F L E K V R-OH.     

Turnover of brain adrenergic transmitters in Quaking mice

Q uaking mice, neurological mutants of the C57 BL/6J strain have a markedly deficient myelination of the CNS(S idman , D ickie and A ppel , 1964). Many studies have been carried out on their lipids (J acque , H arpin and B aumann , 1969; N eskovic , N ussbaum and M andel , 1969, 1970; K urihara , N ussbaum and M andel , 1970; S arlieve , N eskovic and M andel , 1971; S ingh , S pritz and G eyer , 1971) for this reason, but little attention has been paid to other aspects of their aminergic transmitters metabolism. During the course of our work, T illement , D ebarle , S imon and B oissier (1970) reported on the transmitter levels in Quaking mice. The reasons for thinking that the monoamine metabolism of these mice might be altered are as follows. The trembling might be associated with a change in the activity and therefore metabolism of dopaminergic structures. Chronic stress due to permanent tremor might induce changes in norepinephrine metabolism. Since there are changes in the sleep patterns of Quaking mice (V alatx and J ouvet , 1971), there might be changes in brain serotonin metabolism. This study of the turnover of norepinephrine, dopamine and serotonin in the whole brains of control and Quaking mice is the preliminary to detailed examination of the turnover of the transmitters in well-defined brain regions.     

Effects of Soil Nutrients and Moisture on Root/Shoot Ratios in Lolium perenne L. and Trifolium repens L

The dry weights of foliage and roots (excluding stembases) werecompared in a 3³x2² factorial experiment with Lolium perenneL. and Trifolium repens L. grown in pots with three nitrogen(0–300 ppm N), phosphorus (0–300 ppm P), and soilmoisture (pF 3.2, pF 2.4, and waterlogged) treatments, eachduplicated. Root/shoot ratios were influenced significantly (P < 0.001)by N, P, and W (soil moisture), but these main effects werequalified by highly significant first-order interactions andsecond-order interactions which included N and P. The lowestR/S ratios occurred where N, P, and W were all non-limiting,and the highest where there was an imbalance of these factors. The explanation suggested is that a decrease in the availabilityof N, P, or W causes an increase in the relative weight of roots,but in the presence of N, P, or W deficiency an increase inany one of these factors causes a further increase in the R/Sratio by increasing the relative efficiency of the foliage.     

A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

Although mutations in the melanocortin-4 receptor (MC4R) gene cause severe early-onset obesity, we still do not have effective approaches to correct the defects of these mutations. Several antagonists have been identified as pharmacoperones of the MC4R whereas no agonist of the MC4R has been reported. In the present study, we investigated the effect of a small molecule agonist of the MC4R, THIQ, on the cell surface expression and signaling of ten intracellularly retained MC4R mutants using different cell lines. We showed that THIQ increased the cell surface expression of three mutants (N62S, C84R, and C271Y) and two of them (N62S and C84R) had increased signaling in HEK293 cells. Interestingly, THIQ increased the signaling of two other mutants (P78L and P260Q) without increasing their cell surface expression in HEK293 cells. In neuronal cells, THIQ exhibited a more potent effect, correcting the cell surface expression and signaling of seven mutants (N62S, I69R, P78L, C84R, W174C, P260Q, and C271Y). Other mutants were not rescued by THIQ. We also showed that THIQ did not rescue MC4R mutants defective in ligand binding or signaling or one intracellularly retained mutant of the melanocortin-3 receptor. In summary, we demonstrated that a small molecule agonist acted as a pharmacoperone of the MC4R rescuing the cell surface expression and signaling of some intracellularly retained MC4R mutants.     

Besprechungen

Book Reviewed in this article: Brown, R. G. B. , (1969): Seed selection by Pigeons (Nahrungsauswahl bei Tauben). Neumann, Charles P. , und Peter H. Klopfer (1969): Cage size and discrimination tests in birds: a methodological caution (Der Einfluß der Käfiggröße auf die Lerngeschwindigkeit in Zweifachwahlversuchen). Maley, Michael J. (1969): Electrical stimulation of agonistic behavior in the Mallard (Auslösung artgemäßen agonistischen Verhaltens durch elektrische Hirnreizung bei Stockenten). Behaviour 34 , 138–160. Logan, Frank A. , und Robert Boice (1969): Aggressive behavior of paired Rodents in an avoidance context (Angriffsverhalten je zweier Ratten in der gleichen Dressuranordnung, wo sie den elektrischen Schlag vermeiden lernen sollen). Walther, Fritz R. (1969): Flight behaviour and avoidance of predators in Thomson's Gazelle (Gazella thomsoni Günther 1884) (Fluchtverhalten und Ausweichen vor Raubtieren bei Thomson-Gazellen). Frisch, Karl v. (1969): Leben der Bienen, 8. Aufl., Verständliche Wissenschaft Bd. Nicolai, J. (1969): Tauben: Haltung, Zucht, Arten. Kosmos-Bücherei, Franckh'sche Verlagshandlung. Rüppell, Georg (1969): Beiträge zum Verhalten des Krabbentauchers (Plautus alle alle). J. Orn. 110, 161–169. George, Uwe (1969): über das Tränken der Jungen und andere Lebensäußerungen des Senegalflughuhns, Pterocles senegallus, in Marokko. Thielcke, Gerhard (1969): Die Reaktion von Tannen- und Kohlmeise (Parus ater, P. major) auf den Gesang nah verwandter Formen. Kneutgen, Johannes (1969): Zwei Vögel verschiedener Arten verständigen sich in einer ?Fremdsprache” Beobachtung zur interspezifischen Kommunikation. Ploog, Detlev (1968): Kommunikationsformen bei Affen. Homo 19 , 151–165. Gardner, R. Allen und Beatrice T. (1968): Teaching sign language to a Chimpanzee. Haseloff, O. W. ed. (1969): Kommunikation. Forschung und Information. Lenneberg, Eric H. (1967): Biological Foundation of Language (Biologische Grundlegung der Sprache). Hediger, H. (1968): Exotische Freunde im Zoo. Herder-Bücherei Band 303. Hassenstein, B. (1969): Biologie des Lernens. Garms, Harry (1969): Pflanzen und Tiere Europas, ein Bestimmungsbuch. Johnson, Cecil E. ed. (1968): Social and natural Biology, Selections from contemporary classics (Sozial- und Freilandbiologie, Auswahl aus zeitgenössischen Klassikern).