Effect of Hypoxia on the Function of the Human Serotonin1A Receptor

Abstract

Cellular hypoxia causes numerous pathophysiological conditions associated with the disruption of oxygen homeostasis. Under oxygen-deficient conditions, cells adapt by controlling the cellular functions to facilitate the judicious use of available oxygen, such as cessation of cell growth and proliferation. In higher eukaryotes, the process of cholesterol biosynthesis is intimately coupled to the availability of oxygen, where the synthesis of one molecule of cholesterol requires 11 molecules of O2. Cholesterol is an essential component of higher eukaryotic membranes and is crucial for the physiological functions of several membrane proteins and receptors. The serotonin1A receptor, an important neurotransmitter G protein-coupled receptor associated with cognition and memory, has previously been shown to depend on cholesterol for its signaling and function. In this work, in order to explore the interdependence of oxygen levels, cholesterol biosynthesis, and the function of the serotonin1A receptor, we developed a cellular hypoxia model to explore the function of the human serotonin1A receptor heterologously expressed in Chinese hamster ovary cells. We observed cell cycle arrest at G1/S phase and the accumulation of lanosterol in cell membranes under hypoxic conditions, thereby validating our cellular model. Interestingly, we observed a significant reduction in ligand binding and disruption of downstream cAMP signaling of the serotonin1A receptor under hypoxic conditions. To the best of our knowledge, our results represent the first report linking the function of the serotonin1A receptor with hypoxia. From a broader perspective, these results contribute to our overall understanding of the molecular basis underlying neurological conditions often associated with hypoxia-induced brain dysfunction.