Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1998-12-09
2001-11-13
McGarry, Sean (Department: 1635)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S300000
Reexamination Certificate
active
06316596
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to receptors for peptide hormones which are involved in regulating glucose and/or insulin levels, i.e., in energy homeostasis.
BACKGROUND OF THE INVENTION
Pituitary adenylate cyclase activating polypeptide (PACAP) is the newest member of the superfamily of metabolic, neuroendocrine and neurotransmitter peptide hormones that exert their action through the cAMP-mediated signal transduction pathway (Arimura, 1992
, Regul Peptides
37:287-303). The biologically active peptides are released from the biosynthetic precursor in two molecular forms, either as a 38-amino acid peptide (PACAP-38) and/or as a 27-amino acid peptide (PACAP-27) with an amidated carboxyl termini (Arimura, 1992
, Regul. Peptides
37:287-303).
The highest concentrations of the two forms of the peptide are found in the brain and testis (reviewed in Arimura, supra). They are also expressed in peripheral tissues, such as adrenal gland, stomach and pancreas (Arimura, supra). The shorter form of the peptide, PACAP-27, shows 68% structural homology to vasoactive intestinal polypeptide (VIP). However, the distribution of PACAP and VIP in the central nervous system suggests that these structurally related peptides have distinct neurotransmitter functions (Koves et al., 1991
, Neuroendocrinology
54:159-169). Biochemical and cloning experiments have demonstrated that there are receptors which recognize both PACAP and VIP peptides with similar affinities (reviewed in Harmar and Lutz, 1994
, Trends in Phanm. Sci
. 15:97-99), as well as a receptor that is specific for PACAP-38 and PACAP-27 (PACAP-Type 1receptor) (Christophe, 1993
, Biochim. Biophys. Acta
1154:183-199; Hashimoto et al., 1993
, Neuron
11:333-342).
Despite the rapid progress in identifying the PACAP-Type 1 and the common PACAP/VIP receptors, the role of PACAPs in human physiology remain elusive.
Furthermore, in view of the finding of common PACAP/VIP receptors some of the physiological functions previously attributed to the VIP will need to be reexamined. Recent studies have demonstrated diverse biological effects of PACAP-38, from a role in reproduction (McArdle, 1994
, Endocrinology
135:815-817) to ability to stimulate insulin secretion (Yada et al., 1994
, J. Biol. Chem
. 269:1290-1293).
SUMMARY OF THE INVENTION
In its broadest aspect, the present invention extends to an energy homeostasis peptide hormone receptor having the following characteristics:
(a) expression in mammalian adipocytes;
(b) being coupled to a cAMP-mediated signal transduction pathway; and
(c) binding to pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide.
In a further aspect, the energy homeostasis peptide hormone receptor is also present in the brain, and is widely distributed in peripheral tissues. In one embodiment of the invention, the energy homeostasis peptide hormone receptor is PACAP/VIP R-2, which is distributed in tissues including brain, adipocytes, pancreas, skeletal muscle, stomach, kidney and heart, and in another embodiment, the energy homeostasis peptide hormone receptor is PACAP/VIP R-2B, which is distributed in tissues including brain, adipocytes, skeletal muscle and heart.
In a specific example, the energy homeostasis peptide hormone receptor is encoded. by a nucleotide sequence of approximately 1.8 kb, and encodes a protein of approximately 438 amino acids (PACAP/VIP R-2) or 432 amino acids (PACAP/VIP R-2B). In a particular embodiment, the energy homeostasis peptide hormone receptor is PACAP/VIP R-2 or PACAP/VIP R-2B, which bind PACAP-27, PACAP-38, VIP and secretin. A preferred embodiment of the invention, PACAP/VIP R-2, is encoded by the nucleotide sequence of SEQ ID NO:3, and/or is a PACAP-VIP R-2 having the amino acid sequence of SEQ ID NOS: 1 or 2. In another preferred embodiment of the invention, the energy homeostasis peptide hormone receptor, PACAP/VIP R-2B, has the amino acid sequence of SEQ ID NO:9, and is encoded by the nucleotide sequence of SEQ ID NOS:8 or 10.
In a still further aspect, the present invention extends to methods of using the energy homeostasis peptide hormone receptor as receptor for a metabolic, neuroendocrine and/or neurotransmitter peptide hormone, to control energy homeostasis, including stimulating insulin secretion, and as a modulator of reproductive function.
In a particular embodiment, the present invention relates to all members of the herein disclosed family of energy homeostasis peptide hormone receptors, which have the characteristics of: (a) expression on mammalian adipocytes; (b) being coupled to the cAMP-mediated signal transduction pathway; and (c) binding to pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide.
The present invention also relates to a recombinant DNA molecule or cloned gene, or a degenerate variant thereof, which encodes an energy homeostasis peptide hormone receptor; preferably a nucleic acid molecule, in particular a recombinant DNA molecule or cloned gene, encoding the energy homeostasis peptide hormone receptor and has a nucleotide sequence or is complementary to a DNA sequence shown in
FIG. 6
(SEQ ID NO:3),
FIG. 7
(SEQ ID NO:8) or
FIG. 9
(SEQ ID NOS:3 and 10).
The human and murine DNA sequences of the energy homeostasis peptide hormone receptors of the present invention or portions thereof, may be prepared as probes to screen for complementary sequences and genomic clones in the same or alternate species. The present invention extends to probes so prepared that may be provided for screening cDNA and genomic libraries for the energy homeostasis peptide hormone receptor. For example, the probes may be prepared with a variety of known vectors, such as the phage &lgr; vector. The present invention also includes the preparation of plasmids including such vectors, and the use of the DNA sequences to construct vectors expressing antisense RNA or ribozymes which would attack the mRNAs of any or all of the DNA sequences set forth in
FIG. 6
(SEQ ID NO:3),
FIG. 7
(SEQ ID NO:8) or
FIG. 9
(SEQ ID NOS:3 and 10). Correspondingly, the preparation of antisense RNA and ribozymes are included herein.
The present invention also includes energy homeostasis peptide hormone receptor proteins having the activities noted herein, and that display the amino acid sequences set forth and described above and selected from SEQ ID NOS: 1, 2 and 9.
In a further embodiment of the invention, the full DNA sequence of the recombinant DNA molecule or cloned gene so determined may be operatively linked to an expression control sequence which may be introduced into an appropriate host. The invention accordingly extends to unicellular hosts transformed with the cloned gene or recombinant DNA molecule comprising a DNA sequence encoding the present energy homeostasis peptide hormone receptor(s), and more particularly, the complete DNA sequence determined from the sequences set forth above and in SEQ ID NOS:3, 8 and 10.
According to other preferred features of certain preferred embodiments of the present invention, a recombinant expression system is provided to produce biologically active animal or human energy homeostasis peptide hormone receptor.
The concept of the energy homeostasis peptide hormone receptor contemplates that specific molecules exist for correspondingly specific ligands, such as pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and the like, as described earlier. Accordingly, the exact structure of each energy homeostasis peptide hormone receptor will understandably vary so as to achieve this ligand and activity specificity. It is this specificity and the direct involvement of the energy homeostasis peptide hormone receptor in the chain of events leading to gene activation, that offers the promise of a broad spectrum of diagnostic and therapeutic utilities.
The present invention naturally contemplates several means for preparation of the energy homeostasis peptide hormone receptor, including as illustrated herein known recombinant techniques,
Mojsov Svetlana
Wei Yang
Klauber & Jackson
McGarry Sean
The Rockefeller University
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