Dipeptidyl peptidase IV inhibition potentiates Y2 but not Y1 receptor-mediated absorptive tone in human and mouse colon mucosa

Iain Tough, Helen Cox
King’s College London, London, United Kingdom

The neurotransmitter, neuropeptide Y (NPY) and related hormone, peptide YY (PYY) are metabolized by the enzyme dipeptidyl peptidase IV (DPPIV), the former having a cleavage rate four times faster than the latter (Mentlein et al., 1993). We have demonstrated increases in short-circuit current (Isc), following Y1 and Y2 receptor antagonist pretreatment of human (Cox & Tough, 2002) and mouse (Hyland et al., 2003) colon mucosa, which we attributed to alleviation of anion absorption caused by endogenous PYY or NPY stimulation. Here we investigated whether DPPIV inhibition prolonged or amplified either Y1 or Y2 receptor-mediated tone.

Colonic mucosae from four clinical specimens (3 male and 1 female; 74.2±5.3 yr) or from male wild type mice (>10 wks, C57BL/6-129/SvJ background), were voltage-clamped at 0mV in Ussing chambers as described previously (Cox and Tough, 2002; Cox et al., 2001). Ion transport was measured continuously as Isc (μA.cm-2) and all additions were basolateral. Preparations were pretreated with 1μM DPPIV inhibitor (compound 3, Lankas et al., 2005), 20-30 min prior to addition of the Y1 receptor antagonist BIBO3304 (BIBO; 300nM) or the Y2 receptor antagonist BIIE0246 (BIIE; 1μM). Time-course profiles of the antagonist responses were analysed with the peak responses (recorded 25 min following additions) expressed as mean ± 1s.e.m. and data groups compared using Student’s unpaired t-test.

In human colon mucosa, the DPPIV inhibitor (i) increased basal Isc (79.7±6.5 μA.cm-2;n=20) by 2.8±1.0 μA.cm-2 (n=8; P<0.05), (ii) had no effect on BIBO-mediated increases in Isc (12.1±3.3 μA.cm-2, n=4 cf. controls: 16.1±6.5 μA.cm-2, n=4) and (iii) potentiated peak BIIE responses (29.5±5.9 μA.cm-2, n=4 cf. controls: 9.6±4.7 μA.cm-2, n=4; P<0.05). No differences were observed between BIBO and BIIE response profiles in human mucosa; however in mouse preparations BIBO responses were faster in onset (P<0.01 at 3-5 min) than BIIE. Additionally in mouse mucosa, compound 3 (i) increased basal Isc (16.0±1.9 μA.cm-2; n=30) by 0.6±0.2 μA.cm-2 (n=15; P<0.05), (ii) had no effect on BIBO-mediated increases in Isc (7.7±2.6 μA.cm-2, n=7 cf. controls: 7.7±1.6 μA.cm-2, n=7) and (iii) potentiated peak BIIE responses (17.1±2.6 μA.cm-2, n=8 cf. controls: 8.7±2.3 μA.cm-2, n=8). This data suggests that DPPIV inhibition amplifies NPY-mediated BIIE responses by prolonging the half-life of the neurotransmitter, whereas PYY-mediated BIBO responses are unaffected. Future studies will measure the relative levels of each peptide released from mucosal preparations in the absence or presence of compound 3.


We thank Merck & Co. Inc. (Rahway, N.J.) for the DPPIV inhibitor and the Wellcome Trust for funding.

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