Is PP56 (D-myo-inositol-1,2,6-trisphosphate) an antagonist at neuropeptide Y receptors?

PP56 (D-myo-inositol-1,2,6,-trisphosphate) has been reported to specifically inhibit neuropeptide Y-mediated effects in vasculature, heart and brain; because of its reversible but non-competitive antagonism interaction with neuropeptide Y receptor signalling or allosteric modulation of neuropeptide Y binding have been postulated. These possibilities were tested in the present study. PP56 did not affect [125I]neuropeptide Y binding to HEL- or SK-N-MC-cells or to porcine splenic membranes. PP56 did not inhibit neuropeptide Y-stimulated Ca2+ increases in HEL- or SK-N-MC-cells or in cultured porcine aortic vascular smooth muscle cells but if anything slightly enhanced it. PP56 did not antagonize the neuropeptide Y-mediated inhibition of forskolin-stimulated cAMP accumulation in HEL-cells. We conclude that previously reported antagonistic effects of PP56 occur distal to the neuropeptide Y receptor or its second messenger systems Ca2+ and cAMP or may be restricted to neuropeptide Y receptors in certain model systems.