Neuropeptide Receptor Laboratory

Laboratory Head

Dr Ross AD Bathgate BSc (Hons) PhD (UQ)

Contact Details

Email:

ross.bathgate@florey.edu.au

Phone:

+61 (0)3 8344 5648

Fax:

+61 (0)3 9348 1707

Number of

Staff:        2

Students:  5

Research Interests

The peptide hormones relaxin, relaxin-3 and insulin-like peptide 3 (INSL3) have numerous essential biological roles. Relaxin induces its effects by regulating collagen turnover, stimulating tissue growth and angiogenesis and inducing blood vessel dilatation. It is currently in clinical trials for cervical ripening, preeclampia and congestive heart failure. INSL3 is essential for germ cell maturation and has considerable potential as a fertility regulator in both males and females. Recent studies from our laboratory with INSL3 receptor antagonists have highlighted their potential use as male contraceptives. Relaxin-3 is a specific neuropeptide which our laboratory recently discovered and has potential roles in feeding and stress responses. We are working with industry partners (Organon, Johnson and Johnson, BAS Biomedical) to determine the biological roles of the peptides and exploit their clinical potential.

The receptors for these peptides are all G-protein coupled receptors (GPCRs) which are the largest class of cell surface signalling molecules and major drug targets. The receptors for relaxin and INSL3 are the leucine rich-repeat containing G-protein coupled receptors (GPCRs), LGR7 and LGR8 respectively. Relaxin-3 interacts with an unrelated receptor, GPCR135, but it will also bind to and activate GPCR142, the receptor for INSL5, as well as LGR7. We are using various pharmacological techniques to determine the ligand binding specificities of the various receptors as well their cell signalling characteristics. Determining the pharmacological specificities of the receptors will assist in developing small molecules that will mimic peptide action for clinical use.

Additionally, we are studying the basic pharmacology of these novel GPCRs including their potential functional homo- and hetero-dimerisation. We have also identified numerous receptor splice variants which are modulators of receptor function and potentially act as receptor antagonists. These studies have the potential to lead the development of novel drugs to activate or block receptor function.

Current Projects

PhD and Honours projects are available to study the expression, structure and function of these novel receptors and their splice variants. Candidates will undergo training in various techniques including molecular cloning, cell biology, protein chemistry, site-directed mutagenesis, viral expression and animal behavioural phenotyping. Furthermore, candidates will be able to interact with industry partners with the opportunity to commercialise any of their research outcomes.

Funding

Selected Recent Publications

Please see PubMed.

Bathgate RAD, Ivell R, Sanborn BM, Sherwood OD and Summers RJ (2006) International union of pharmacology (IUPHAR); Recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacological Reviews 58: 7-31.

Scott D, Layfield S, Hsueh A, Tregear GW and Bathgate RAD (2006) Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique LDLa modules. Journal of Biological Chemistry 281: 34942-34954.

Hopkins EJ, Layfield S, Ferraro T, Bathgate RA, Gooley PR. (2006) The NMR solution structure of the relaxin (RXFP1) receptor LDLa module and identification of key residues in the N-terminal region of the module that mediate receptor activation. Journal of Biological Chemistry, Dec 4; [Epub ahead of print]

Bathgate RAD, Lin F, Hanson NF, Otvos, Jr. L, Guidolin A, Giannakis C, Bastiras S, Layfield S, Ferraro T, Ma S, Zhao C, Gundlach AL, Samuel CS, Tregear GW, Wade JD (2006) Improved regioselective disulfide bond synthesis and biological characterization of human relaxin-3. Biochemistry 45: 1043-1053

Muda M, He C, Martini PGV, Ferraro T, Layfield S, Taylor D, Chevrier C, Schweickhardt R, Kelton C, Ryan PL and Bathgate RAD (2005) Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Molecular Human Reproduction 11: 591-600.

Del Borgo M, Hughes AR, Bathgate RAD, Lin F, Kawamura K and Wade JD (2006) Conformationally constrained mimetics of insulin-like peptide 3 B-chain are specific LGR8 antagonists. Journal of Biological Chemistry 281: 13068-13074.

Research