| 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 intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to G(s) and G(q), whereas CCK2R primarily couples to G(q). Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-G(s) signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-G(q) complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.
Structural insights into human brain-gut peptide cholecystokinin receptors.,Ding Y, Zhang H, Liao YY, Chen LN, Ji SY, Qin J, Mao C, Shen DD, Lin L, Wang H, Zhang Y, Li XM Cell Discov. 2022 Jun 7;8(1):55. doi: 10.1038/s41421-022-00420-3. PMID:35672283[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
- ↑ Ding Y, Zhang H, Liao YY, Chen LN, Ji SY, Qin J, Mao C, Shen DD, Lin L, Wang H, Zhang Y, Li XM. Structural insights into human brain-gut peptide cholecystokinin receptors. Cell Discov. 2022 Jun 7;8(1):55. PMID:35672283 doi:10.1038/s41421-022-00420-3
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