Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1994-05-26
1996-11-05
Walsh, Stephen G.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 701, 435 703, 536 231, 536 235, C12N 1512
Patent
active
055716954
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage filed under 35 USC 371 of PCT/AU92/00600 filed Nov. 6, 1991.
FIELD OF THE INVENTION
The present invention relates to cDNA and genomic DNA sequences which encode the human neuropeptide Y-Y1 receptor. In addition the present invention relates to the use of these sequences in the production of the human neuropeptide Y-Y1 receptor and related receptor subtypes using recombinant DNA technology and to methods of screening and testing compounds for neuropeptide Y (NPY) agonist or antagonist activity.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) has a wide range of functions in the body, particularly affecting the cardiovascular system. Within the peripheral nervous system NPY is present in postganglionic sympathetic nerves, being co-localised and co-released with other neurotransmitter, including catecholamines. When used pharmacologically, NPY has been shown to have a potent vasoconstrictor activity as well as dramatically potentiating the vasoconstriction caused by many other pressor agents. Particularly high concentrations of NPY are found in the sympathetic nerves supplying the coronary, cerebral and renal vasculature and when infused into these vascular beds, NPY causes prolonged vasoconstriction that is not reversed by adrenergic blocking agents. These observations have led to the proposal that NPY is the candidate transmitter for pathological vasospasm, a major cause of morbidity and mortality when involving the coronary and cerebral vessels.
NPY also appears to be involved in interaction with the renin angiotensin system. NPY containing sympathetic nerve terminals are found on the juxta-glomerular apparatus of the renal cortex and NPY influences renin release. These data, together with the demonstration of alterations in NPY concentrations in hypertensive animal models and the pressor response to infusion of the peptide, have resulted in implications of this peptide in hypertension.
Within the central nervous system NPY is localised predominantly within interneurons where it appears to have a regulatory role. It therefore has widespread and diverse effects including effects on memory and a possible role in Alzheimer's disease. NPY is the most potent known substance to cause an increase in feeding and may play a role in the genetic basis of Type II diabetes mellitus. NPY may also play a role as a regulatory agent in pituitary function as well as potential neuromodulatory function in stress responses and in reproductive function.
Specific agonists and antagonists of NPY are therefore likely to be of substantial benefit for therapy of a wide range of clinical disorders. As NPY possess a compact tertiary structure and different parts of the molecule are required for interaction with different subtypes of the receptor, the logical development of both agonists and antagonists is critically dependent upon the availability and knowledge of specific receptor structure.
NPY binds specifically to at least two receptors, Y1 and Y2. (Fuhlendorff, J., et al., Proc. Natl. Acad. Sci. U.S.A. 87:182-186, 1990). In addition, a third receptor subtype has been suggested (Wahlstedt, et al, Life Sciences 50:PL7-PL12, 1991; Michel, MC Trends in Pharmacol. Sci. 12:389-394, 1991). While it has been demonstrated that NPY receptors couple to the adenylate cyclase second messenger system, it remains probable that additional NPY receptor subtypes exist since there is evidence that phosphatidylinositol turnover, cations, and arachidonic acid may also function ask second messengers for NPY. Since NPY agonists and antagonists may have commercial value as potential anti-hypertensive agents, cardiovascular drugs, neuronal growth factors, anti-psychotics, anti-obesity and anti-diabetic agents, the ability to produce NPY receptors by recombinant DNA technology would be advantageous.
The present invention have isolated full length cDNA clones encoding the human Y1 NPY receptor (designated Y1) from human hippocampal cDNA using DNA homology screening. The receptor sequences were identified as the h
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Herzog Herbert
Selbie Lisa
Shine John
Garvan Institute of Medical Research
Gucker Stephen
Walsh Stephen G.
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