| Structural highlights
Function
[GASR_HUMAN] Receptor for gastrin and cholecystokinin. The CKK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.[1] [2] [3] [4] [5] [6] Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism.[7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
The structure of the third extracellular loop of the human cholecystokinin-2 receptor, CCK2-R(352-379), and its interactions with the C-terminal octapeptide of cholecystokinin (CCK-8) have been determined by high-resolution NMR and computer simulations. In the presence of dodecylphosphocholine micelles, the structure of the receptor fragment consisted of three helices, with the first and third corresponding to residues of the extracellular ends of transmembrane helices (TM) 6 and 7, respectively. The central, extracellular helix, consisting of residues 363-368, was found to be closely associated with the membrane mimetic used during the spectroscopic studies and molecular dynamics (MD) simulations. Upon titration of CCK-8 to the receptor domain, chemical shift perturbation and intermolecular NOEs (Trp30, Met31 of CCK-8 and P371, F374 of CCK2-R) indicated the formation of a stable complex and specific ligand/receptor interactions. Using the NOE-generated intermolecular contact points, extensive MD simulations of CCK-8 bound to the CCK2 receptor were carried out. The results, with CCK-8 in close proximity to TM7, differ from previous structural studies of CCK-8 association with CCK1-R, in which the ligand formed a number of interactions with TM6. These differences may play a role in the ligand specificity displayed by the CCK1 and CCK2 receptor subtypes.
Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin-2 receptor.,Giragossian C, Mierke DF Biochemistry. 2002 Apr 9;41(14):4560-6. PMID:11926817[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ito M, Matsui T, Taniguchi T, Tsukamoto T, Murayama T, Arima N, Nakata H, Chiba T, Chihara K. Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin. J Biol Chem. 1993 Aug 25;268(24):18300-5. PMID:8349705
- ↑ Herget T, Sethi T, Wu SV, Walsh JH, Rozengurt E. Cholecystokinin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer through CCKA and CCKB/gastrin receptors. Ann N Y Acad Sci. 1994 Mar 23;713:283-97. PMID:8185170
- ↑ Ito M, Iwata N, Taniguchi T, Murayama T, Chihara K, Matsui T. Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene. Cell Growth Differ. 1994 Oct;5(10):1127-35. PMID:7848914
- ↑ Hellmich MR, Rui XL, Hellmich HL, Fleming RY, Evers BM, Townsend CM Jr. Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem. 2000 Oct 13;275(41):32122-8. PMID:10913157 doi:http://dx.doi.org/10.1074/jbc.M005754200
- ↑ Schmitz F, Schrader H, Otte J, Schmitz H, Stuber E, Herzig K, Schmidt WE. Identification of CCK-B/gastrin receptor splice variants in human peripheral blood mononuclear cells. Regul Pept. 2001 Sep 15;101(1-3):25-33. PMID:11495676
- ↑ Sethi T, Herget T, Wu SV, Walsh JH, Rozengurt E. CCKA and CCKB receptors are expressed in small cell lung cancer lines and mediate Ca2+ mobilization and clonal growth. Cancer Res. 1993 Nov 1;53(21):5208-13. PMID:8221657
- ↑ Ito M, Matsui T, Taniguchi T, Tsukamoto T, Murayama T, Arima N, Nakata H, Chiba T, Chihara K. Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin. J Biol Chem. 1993 Aug 25;268(24):18300-5. PMID:8349705
- ↑ Herget T, Sethi T, Wu SV, Walsh JH, Rozengurt E. Cholecystokinin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer through CCKA and CCKB/gastrin receptors. Ann N Y Acad Sci. 1994 Mar 23;713:283-97. PMID:8185170
- ↑ Ito M, Iwata N, Taniguchi T, Murayama T, Chihara K, Matsui T. Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene. Cell Growth Differ. 1994 Oct;5(10):1127-35. PMID:7848914
- ↑ Hellmich MR, Rui XL, Hellmich HL, Fleming RY, Evers BM, Townsend CM Jr. Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem. 2000 Oct 13;275(41):32122-8. PMID:10913157 doi:http://dx.doi.org/10.1074/jbc.M005754200
- ↑ Schmitz F, Schrader H, Otte J, Schmitz H, Stuber E, Herzig K, Schmidt WE. Identification of CCK-B/gastrin receptor splice variants in human peripheral blood mononuclear cells. Regul Pept. 2001 Sep 15;101(1-3):25-33. PMID:11495676
- ↑ Sethi T, Herget T, Wu SV, Walsh JH, Rozengurt E. CCKA and CCKB receptors are expressed in small cell lung cancer lines and mediate Ca2+ mobilization and clonal growth. Cancer Res. 1993 Nov 1;53(21):5208-13. PMID:8221657
- ↑ Giragossian C, Mierke DF. Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin-2 receptor. Biochemistry. 2002 Apr 9;41(14):4560-6. PMID:11926817
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