Secretin receptor family explained

Secretin receptor family (class B GPCR subfamily^[1]) consists of secretin receptors regulated by peptide hormones from the glucagon hormone family. The family is different from adhesion G protein-coupled receptors.^[2]

The secretin-receptor family of GPCRs include vasoactive intestinal peptide receptors and receptors for secretin, calcitonin and parathyroid hormone/parathyroid hormone-related peptides. These receptors activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. The receptors in this family have seven transmembrane helices,^{[3] [4]} like rhodopsin-like GPCRs. However, there is no significant sequence identity between these two GPCR families and the secretin-receptor family has its own characteristic 7TM signature.^[5]

The secretin-receptor family GPCRs exist in many animal species. Data mining with the Pfam signature has identified members in fungi, although due to their presumed non-hormonal function they are more commonly referred to as Adhesion G protein-coupled receptors, making the Adhesion subfamily the more basal group.^[6] Three distinct sub-families (B1-B3) are recognized.

Subfamily B1

Subfamily B1 contains classical hormone receptors, such as receptors for secretin and glucagon, that are all involved in cAMP-mediated signalling pathways.

• Pituitary adenylate cyclase-activating polypeptide type 1 receptor
  • PACAPR (ADCYAP1R1)
• Calcitonin receptor
  • CALCR
    • Corticotropin-releasing hormone receptor CRHR1; CRHR2
• Glucose-dependent insulinotropic polypeptide receptor/Gastric inhibitory polypeptide receptor
  • GIPR
    • Glucagon receptor GCGR
    • Glucagon receptor-related GLP1R; GLP2R;
• Growth hormone releasing hormone receptor
  • GHRHR
• Parathyroid hormone receptor
  • PTHR1; PTHR2
• Secretin receptor
  • SCTR
    • Vasoactive intestinal peptide receptor VIPR1; VIPR2

Subfamily B2

Subfamily B2 contains receptors with long extracellular N-termini, such as the leukocyte cell-surface antigen CD97; calcium-independent receptors for latrotoxin and brain-specific angiogenesis inhibitor receptors amongst others. They are otherwise known as Adhesion G protein-coupled receptors.

• • • Brain-specific angiogenesis inhibitor BAI1; BAI2; BAI3
• CD97 antigen
  • CD97
    • EMR hormone receptor CELSR1; CELSR2; CELSR3; EMR1; EMR2; EMR3; EMR4
    • GPR56 orphan receptor GPR56; GPR64; GPR97; GPR110; GPR111; GPR112; GPR113; GPR114; GPR115; GPR123; GPR125; GPR126; GPR128; GPR133; GPR144; GPR157
    • Latrophilin receptor ELTD1; LPHN1; LPHN2; LPHN3
    • Ig-hepta receptor GPR116

Subfamily B3

Subfamily B3 includes Methuselah and other Drosophila proteins. Other than the typical seven-transmembrane region, characteristic structural features include an amino-terminal extracellular domain involved in ligand binding, and an intracellular loop (IC3) required for specific G-protein coupling.

Unclassified members

HCTR-5

HCTR-6; KPG 006; KPG 008

Notes and References

1. Harmar AJ . Family-B G-protein-coupled receptors . Genome Biology . 2 . 12 . REVIEWS3013 . 2001 . 11790261 . 138994 . 10.1186/gb-2001-2-12-reviews3013 . free .
2. 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 . 6 . International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors . Pharmacological Reviews . 67 . 2 . 338–67 . 2015 . 25713288 . 4394687 . 10.1124/pr.114.009647 .

3. Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC . 6 . Structure of the human glucagon class B G-protein-coupled receptor . Nature . 499 . 7459 . 444–9 . July 2013 . 23863937 . 3820480 . 10.1038/nature12393 . 2013Natur.499..444S .

4. Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, Liu K, Cai X, Dai A, Lin G, Liu D, Wu F, Wu Y, Zhao S, Ye L, Han GW, Lau J, Wu B, Hanson MA, Liu ZJ, Wang MW, Stevens RC . 6 . Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators . Nature . 546 . 7657 . 312–315 . June 2017 . 28514449 . 10.1038/nature22378 . 2017Natur.546..312S . 2141649 .

5. Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC . Insights into the structure of class B GPCRs . Trends in Pharmacological Sciences . 35 . 1 . 12–22 . January 2014 . 24359917 . 3931419 . 10.1016/j.tips.2013.11.001 .
6. Krishnan A, Almén MS, Fredriksson R, Schiöth HB . The origin of GPCRs: identification of mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in fungi . PLOS ONE . 7 . 1 . e29817 . 2012 . 22238661 . 3251606 . 10.1371/journal.pone.0029817 . Xue C . 2012PLoSO...729817K . free .