Constitutive activity of the sweet taste receptor: Heavy water sweetness and beyond

The present work proposes an explanation for a recent observation that has conclusively proven that heavy water, that is, water containing the non-radioactive isotope of hydrogen deuterium, is mildly sweet, at variance with the tasteless common water. No firm explanation was proposed for this unexpected behavior. Yet, the subject is far from being an irrelevant curiosity, as the explanation of yet unidentified properties of the sweet receptor can help us to understand the molecular bases of food appreciation that have direct repercussions on pathologies such as diabetes and obesity. Here, a simple but convincing structural explanation of the taste of heavy water is proposed that is based on the influence of heavy water on the conformation of the active form of the receptor. The explanation requires the concept of "constitutive receptor activity", that is, a notion well accepted in many areas of pharmacology but clearly neglected in reference to taste receptors. We discuss how constitutive activity also explains other properties such as the recognition of sweet proteins that are several thousand times sweeter than small carbohydrates.