Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1991-09-03
1994-02-22
Wax, Robert A.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 71, 435 721, 435 737, 435 691, 4352402, 4352523, 4353201, 530350, 530359, 5303871, 530397, 530403, 536 231, 536 235, 536 2431, C12Q 168, C12P 2106, C07K 300, C07H 1512
Patent
active
052886077
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to polypeptides having a .beta.-adrenergic receptor activity in man, and more particularly implicated in the lipolytic response of the adipose tissues, and the genes coding for these polypeptides.
The invention also relates:
to vectors containing the genes coding for polypeptides having a .beta.-adrenergic activity,
to cell hosts transformed by genes coding for the above-mentioned polypeptides,
to nucleotide probes capable of hybridizing with the genes coding for the above-mentioned polypeptides,
to polyclonal and monoclonal antibodies directed against the above-mentioned polypeptides and which can be used for the purpose of in vitro diagnosis,
to kits for studying the degree of affinity of certain substances for the above-mentioned polypeptides,
to medicines containing substances active on the above-mentioned polypeptides having a .beta.-adrenergic receptor activity, and more particularly designed for the treatment of obesity, diabetes and hyperlipidemia.
BACKGROUND OF THE INVENTION
The catecholamines such as adrenalin and noradrenalin, the synthetic agonists of these catecholamines which mimic their biological function and the antagonists which block these functions exert their effects by binding to specific recognition sites (adrenergic receptors) situated on cell membranes.
Two main classes of adrenergic receptors have been defined, the .alpha. adrenergic receptors and the .beta. adrenergic receptors.
Within the set of these two classes, four sub-types of these receptors for catecholamines are distinguished (.alpha.1, .alpha.2, .beta.1 and .beta.2-AR). Their genes have recently been isolated and identified (5-8). The analysis of these genes has made it possible to recognize that they belong to a family of integral membrane receptors exhibiting certain homologies (9-10), in particular at the level of the 7 transmembrane regions. These latter are coupled to regulatory proteins, called G proteins, capable of binding molecules of guanosine triphosphate (GTP).
More precisely, the G proteins are proteins having the capacity to intervene structurally and functionally between receptors and enzymes catalysing the production of intracellular mediators (such as adenylate cyclase, guanylate cyclase, the phospholipases, the kinases) or between receptors and ion channels, the controlled opening of which brings about a flux of ions (such as calcium, potassium, sodium, hydrogen ions) into the cell.
These proteins have transduction and coupling functions.
The above-mentioned family of receptors is designated as the "R.sub.7 G family" (10). It comprises, in particular, acetylcholine muscarinic receptors, serotonin receptors, receptors for neuropeptides, substance K and angiotensin II and the visual receptors for the family of the opsins (9-10).
Up until very recently, the definition of the sub-types of receptors was based mainly on the analysis of the physiological properties and binding of different ligands in heterogenous systems. In the R.sub.7 G family, several genes coding for sub-types of receptors defined by their pharmacological properties have been cloned and characterized. Probes obtained from these genes have made it possible to identify additional receptor sub-types (11-12).
The precise nature of the .beta.-adrenergic receptor, which is capable of modulating physiological functions such as thermogenesis in adipose cells as well as intestinal relaxation has remained obscure. In connection with this latter property, it has been found that isoproterenol still inhibits the contractions of the guinea pig ileum induced by the cholinergic pathway (3), in spite of the total blockage of the known adrenergic receptors of the .alpha. and .beta. types with pentholamine and propanolol.
By undertaking a detailed study of the physiological effects of the agonists and of the inhibition by the antagonists of the polypeptides having a .beta.-adrenergic receptor activity (1-3), the hypothesis has been put forward of the existence of a novel sub-type of .beta.-adrenergic
REFERENCES:
Bahouth et al. "Subclassification of .beta.-Adreng. Recept. . . ." Molecular Pharmacology 34:318-326 1988.
Arch et al. "Atypical .beta.-adrenoreceptor on brown . . . " Nature vol. 309 pp. 163-165 (1984).
Emorine et al. "Structure of the gene for human .beta..sub.2 -adrenergic . . . " PNAS vol. 84 pp. 6995-6999 (1987).
Yarden et al. "Avian .beta.-adrenergic receptor: Primary Structure. . . " PNAS vol. 83, pp. 6795-6799 (1986).
Lerner; Richard "Tapping the immunological repertoire . . ." Nature vol. 299 pp. 592-596 (Oct. 14, 1982).
Emorine Laurent
Marullo Stefano
Strosberg Donny
Centre National de la Recherche Scientifique
Kim Hyosuk
Wax Robert A.
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