Compensatory changes in [125I]-PYY binding in Y receptor knockout mice suggest the potential existence of further Y receptor(s)

Gene knockout approaches have helped to better understand the functions of the different Y receptors. However, some results obtained from these knockout mice are unexpected and differ from the results of pharmacological intervention experiments. One possible explanation for this is that germ-line gene deletion of a particular Y receptor can influence expression and function of the remaining Y receptors. Here we show that such compensation in mRNA and protein expression does occur in Y receptor single, double and triple knockout models. Radio-ligand binding experiments using [125I]-PYY revealed significant up- and down-regulation of remaining Y receptor binding sites in various Y receptor knockout models compared to results from control mice employing Y receptor preferring agonist or antagonists for displacement of the radio-ligand. The most obvious change can be seen in the hippocampus of Y1 knockout mice, where the level of the remaining Y receptors is strongly down-regulated. In Y2 knockout mice no such trend can be seen, however, the expression pattern is significantly changed with a strong up-regulation of [125I]-PYY specific binding in the dentate gyrus. Interestingly, this pattern was also seen in Y1Y2Y4 triple knockout mice. Y5 receptor mRNA was approximately 20% higher in the hippocampus and dentate gyrus in the triple knockout mice compared to wild-type controls, while Y6 mRNA expression could not be detected. However, competition binding experiments in Y1Y2Y4 triple knockout mice with the Y5 receptor preferring ligands [Leu31, Pro34] NPY and [A31, Aib32] NPY were able to replace only approximately 50% of [125I]-PYY binding in the dentate gyrus suggesting the existence of further yet unidentified Y receptor(s).