G protein coupled receptor agonists and antagonists and methods of activating and inhibiting G protein coupled receptors using the same

1. A polypeptide comprising:

a) a first domain comprising an intracellular loop, or a fragment thereof, of a G protein coupled receptor (GPCR), wherein said GPCR is a Class A or Class B GPCR, and wherein said fragment comprises at least 3 contiguous amino acid residues of the intracellular loop, and

b) a second domain, attached to the first domain, wherein said second domain comprises a cell-penetrating, membrane-tethering hydrophobic moiety comprising: a tridecanoyl (C 13 ), myristoyl (C 14 ), pentadecanoyl (C 15 ), palmitoyl (C 16 ), phytanoyl (methyl substituted C 16 ), heptadecanoyl (C 17 ), stearoyl (C 18 ), nonadecanoyl (C 19 ), arachidoyl (C 20 ), heniecosanoyl (C 21 ), behenoyl (C 22 ), trucisanoyl (C 23 ), a lignoceroyl (C 24 ), a cholesterol, a phospholipid, a steroid, a sphingosine, a ceramide, an octyl-glycine, a 2-cyclohexylalanine, or a benzolylphenylalanine,

wherein said polypeptide does not comprise an extracellular portion of the GPCR;

and wherein said polypeptide is an agonist or antagonist of said GPCR.

2. The polypeptide of claim 1 , wherein said first domain comprises at least 5 contiguous amino acid residues of the intracellular loop.

3. The polypeptide of claim 1 , wherein said first domain comprises at least 7 contiguous amino acid residues of the intracellular loop.

4. The polypeptide of claim 1 , wherein the first domain comprises 7 to 24 contiguous amino acid residues of the intracellular loop.

5. The polypeptide of claim 1 , wherein the second domain comprises a steroid.

6. The polypeptide of claim 1 , wherein the second domain comprises a moiety that is selected from the group consisting of a cholesterol, a phospholipid, a steroid, a sphingosine, a ceramide, an octyl-glycine, a 2-cyclohexylalanine, and a benzolylphenylalanine.

7. The polypeptide of claim 1 , wherein the second domain comprises a moiety that is selected from the group consisting of a tridecanoyl (C 13 ), myristoyl (C 14 ), pentadecanoyl (C 15 ), palmitoyl (C 16 ), phytanoyl (methyl substituted C 16 ), heptadecanoyl (C 17 ), stearoyl (C 18 ), nonadecanoyl (C 19 ), arachidoyl (C 20 ), heniecosanoyl (C 21 ), behenoyl (C 22 ), trucisanoyl (C 23 ), and a lignoceroyl (C 24 ) moiety.

8. The polypeptide of claim 7 , wherein the second domain comprises a moiety that is a palmitoyl (C 16 ), pentadecanoyl (C 15 ) or myristoyl (C 14 ) moiety.

9. The polypeptide of claim 1 , wherein the G-protein coupled receptor is selected from the group consisting of a luteinizing hormone receptor, a follicle stimulating hormone receptor, a thyroid stimulating hormone receptor, a calcitonin receptor, a glucagon receptor, a glucagon-like peptide 1 receptor (GLP-1), a metabotropic glutamate receptor, a secretin receptor, a growth hormone releasing factor (GRF) receptor, a protease-activated receptor (PAR), a cholecystokinin receptor, a somatostatin receptor, a melanocortin receptor, an ADP receptor, an adenosine receptor, a thromboxane receptor, a platelet activating factor receptor, an adrenergic receptor, a 5-HT receptor, CXCR4, CCR5, a chemokine receptor, a neuropeptide receptor, an opioid receptor, a parathyroid hormone (PTH) receptor, a vasoactive intestinal peptide (VIP) receptor, a C5a anaphylatoxin receptor, an Fmet-leu-phe receptor, an APJ receptor, a Cannabis receptor, a lysosphingolipid receptor, an LPA (EDG) receptor, RDC1, and a gastric inhibitory peptide receptor.

10. The polypeptide of claim 1 , wherein said G-protein coupled receptor is a mammalian G-protein coupled receptor.

11. The polypeptide of claim 10 , wherein said G-protein coupled receptor is a protease-activated receptor (PAR).

12. The polypeptide of claim 11 , wherein the protease-activated receptor is selected from the group consisting of PAR 1, PAR2, and PAR4.

13. The polypeptide of claim 1 , wherein said G-protein coupled receptor is selected from the group consisting of Cholecystokinin A (CCKA) receptor, Cholecystokinin B (CCKB) receptor, Somatostatin Receptor Subtype 2 (SSTR2), and Substance P (SubP) receptor.

14. The polypeptide of claim 1 , further comprising a third domain, said third domain being a cell-penetrating, membrane-tethering moiety attached to said first domain.

15. The polypeptide of claim 1 , wherein the polypeptide further comprises 1-15 contiguous amino acid residues of a naturally-occurring transmembrane helix region of the GPCR immediately adjacent to the intracellular loop.

16. The polypeptide of claim 1 , wherein said polypeptide further comprises 1-7 contiguous amino acid residues of a transmembrane helix region of the GPCR.

17. The polypeptide of claim 1 , wherein the cell-penetrating, membrane-tethering hydrophobic moiety is attached to N-terminal amino acid residue of said first domain.

18. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of an adrenergic receptor and an adenosine receptor.

19. The polypeptide of claim 1 , wherein said G protein coupled receptor is an APJ receptor.

20. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of a C5a anaphylatoxin receptor, a chemokine receptor, a lysosphingolipid receptor, an LPA (EDG) receptor, and an Fmet-leu-phe receptor.

21. The polypeptide of claim 20 , wherein said chemokine receptor is selected from the group consisting of a CXCR4 receptor, a CCR5 receptor, and a RDC1 receptor.

22. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of an ADP receptor, a thromboxane receptor, and a platelet activating factor receptor.

23. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of a calcitonin receptor and a parathyroid hormone receptor.

24. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of a glucagon receptor, a glucagon-like peptide 1 receptor (GLP-1), a gastric inhibitory peptide receptor, a vasoactive intestinal peptide receptor, a secretin receptor, a thyroid stimulating hormone receptor, a cholecystokinin receptor, and a growth hormone releasing factor receptor (GFR).

25. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of a luteinizing hormone receptor and a follicle stimulating hormone receptor.

26. The polypeptide of claim 1 , wherein said G protein coupled receptor is selected from the group consisting of a 5-HT receptor, a Cannabis receptor, a neuropeptide receptor, a somatostatin receptor, a melanocortin receptor and an opioid receptor.

27. The polypeptide of claim 1 , wherein said G protein coupled receptor is a metabotropic glutamate receptor.

28. The polypeptide of claim 1 , wherein said GPCR is a Class A GPCR.

29. The polypeptide of claim 1 , wherein said GPCR is a Class B GPCR.

30. The polypeptide of claim 1 , wherein the second domain comprises a palmitoyl (C 16 ) moiety.

31. The polypeptide of claim 1 , wherein the second domain comprises a pentadecanoyl (C 15 ) moiety.

32. The polypeptide of claim 1 , wherein the second domain comprises a myristoyl (C 14 ) moiety.

33. The polypeptide of claim 1 , wherein the second domain comprises a cholesterol.