Adhesion GPCRs
GPCRs represent the largest superfamily of receptors in the human genome. Present on every cell and responding to a plethora of stimuli, GPCRs are involved in a great variety of physiological processes. According to the GRAFS classification, GPCRs can be devided into five classes named Glutamate, Rhodopsin, Adhesion, Frizzled/Taste, and Secretin. By far largest and best understood is the Rhodopsin class that includes all classical GPCRs as well as hundreds of olfactory receptors.
The Adhesion class comprises 33 members in humans with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumors. Most notable is the molecular structure that sets Adhesion GPCRs apart from other GPCR. Intramolecular processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix gives rise to a membrane-spanning and an extracellular subunit, which subsequently reassociate non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. The extracellular subunits of Adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Ligand profiles and in vitro studies have indicated a role of Adhesion GPCRs in cell adhesion and migration. More recent work utilizing genetic models confined this concept by demonstrating that the primary function of Adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of Adhesion GPCRs in tumor cell metastasis.
Selected reading
Bassilana F, Nash M, Ludwig MG. Adhesion G protein-coupled receptors: opportunities for drug discovery. Nat Rev Drug Discov. 2019 Nov;18(11):869-884. PMID: 31462748.
Purcell RH, Hall RA. Adhesion G protein-coupled receptors as drug targets. Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:429-449. PMID: 28968187.
Langenhan T, Schöneberg T eds. (2016) Adhesion G Protein-coupled Receptors. Molecular, Physiological and Pharmacological Principles in Health and Disease. Springer Natura. ISBN 978-3-319-41523-9
Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 2015 Apr;67(2):338-67. PubMed PMID: 25713288.
Langenhan T, Aust G, Hamann J. Sticky signaling–adhesion class G protein-coupled receptors take the stage. Sci Signal. 2013 May 21;6(276):re3. PubMed PMID: 23695165.
Yona S, Stacey M eds. (2010) Adhesion‑GPCRs. Structure to Function. Landes Bioscience & Springer. ISBN: 978-1-4419-7912-4.
Yona S, Lin HH, Siu WO, Gordon S, Stacey M. Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci. 2008 Oct;33(10):491-500. PubMed PMID: 18789697.
Lagerström MC, Schiöth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008 Apr;7(4):339-57. PubMed PMID: 18382464.
Research consortia
DFG Research Unit 2149: Elucidation of Adhesion GPCR signaling This scientific network, established by the German Research Foundation at universities in Leipzig (Aust, Langenhan, Liebscher, Prömel, Scholz, Schöneberg, Sträter), Würzburg (Kittel), Mainz (Wolfrum), Erlangen-Nuremberg (Engel), Heidelberg (Pabst), Amsterdam (Hamann), and New York (Placantonakis) for the period 2015-2020, will seek answers to the questions: “What do Adhesion GPCRs recognize? How do they translate stimuli into a cellular response? And what happens when they are missing?” The speaker and coordinator of the initiative is Tobias Langenhan.