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. 2010 Jun 9;11(6):532–542. doi: 10.1016/j.cmet.2010.04.014

Figure 2.

Figure 2

Colonic Responses to Gpr119 Agonists Are Y1 Receptor Mediated in Mouse and Human Colon Mucosae

(A) Concentration response curve for apical PSN632408 (632, n = 3–14), with two concentration data points only for apical PSN375963 (375, n = 4–5) and OEA (n = 4–5) in WT mouse colon mucosa. Values are the mean ±SEM throughout.

(B) Apical PSN632408 (10 μM) responses after pretreatment with either compound 3 (+Cpd 3, 1 μM) or the Y1 antagonist, BIBO3304 (+BIBO, 300 nM), or Y2 antagonism with BIIE0246 (+BIIE, 1 μM) alone or together with BIBO3304 (+Both). Data groups (mean − SEM) are compared with control PSN632408 responses (Con). ∗∗p ≤ 0.01.

(C) Three different agonists (all apical, 10 μM) stimulate Gpr119 responses in WT colon (n = 5 or 14) and NPY−/− (n = 3–4), but not PYY−/− colon (n = 3–4) or NPYPYY−/− colon (n = 4). Dashed lines show the mean vehicle control values (n = 3–4). Agonist responses in peptide knockouts are compared with WT responses. ∗p ≤ 0.05, ∗∗∗p ≤ 0.001.

(D) Representative Gpr119 responses in human colon mucosa to apical (Ap) or basolateral (Bl) addition of PSN632408 (10 μM). Basal Isc values are shown to the left of each trace, and the mucosal area was 0.64 cm2.

(E) PSN632408 (10 μM) sensitivity to pretreatments with the DPP-IV inhibitor, compound 3 (+Cpd3, 1 μM), GLP-1 antagonist exendin(9-39) (+9-39, 1 μM), Y1 receptor antagonist BIBO3304 (+BIBO, 300 nM), Y2 antagonist BIIE0246 alone (+BIIE, 1 μM), Y2 antagonist BIIE0246 together with BIBO3304 (+Both), and BIIE0246 together with BIBO3304 and exendin(9-39) (+9-39 Both, n = 3–5). Comparisons are made with control PSN632408 responses (Con). ∗p ≤ 0.05, ∗∗∗p ≤ 0.001.

(F) Single concentration (10 μM) effects of apical PSN632408 (632), PSN375963 (375), or OEA (all n = 4) with the mean vehicle controls (dashed line) in normal human colon mucosa. Table S1 includes basal electrophysiological parameters for mouse and human colon mucosal preparations used in this study. Figures S3A–S3C show that PSN632408 and OEA responses are insensitive to blockade of PPARα receptors and TRPV1 desensitization by capsaicin in WT and NPY−/− colon.