Mechanosensitive Ion Channels Modulation by Membrane Composition

Project Summary Our current research focuses on investigating the mechanisms by which fatty acids (the building blocks of the plasma membrane) modulate the function of mechanosensitive ion channels. These ion channels transduce mechanical stimuli into electrochemical signals in all kingdoms of life. Members of the mechanosensitive ion channel family (including the PIEZO channels) are involved in various physiological processes, including gentle touch sensation, proprioception, musculoskeletal development, neuronal differentiation, cell volume, wound healing, and food sensation. PIEZO channel dysfunction has a detrimental effect on human balance, proprioception, skeletal development, mechanical allodynia, and erythrocyte volume. Since PIEZO channels play critical roles in health and disease, it has become clear that modulating their function could have therapeutic effects for a wide range of pathologies. Unfortunately, the pharmacology of PIEZO channels is in its infancy. Hence, we envision that strategies fine-tuning PIEZO channel function will lay the groundwork for novel pharmacological tools. In the past five years, we have identified dietary fatty acids that, when enriched in the plasma membrane, fine-tune PIEZO channel mechanical responses in vitro, ex vivo, and in vivo. Noteworthy, we have utilized fatty acid-enriched diets to ameliorate the deficits associated with increased or reduced PIEZO2 function in mouse models of neurological disorders. Our goals for the next five years are to depict the molecular mechanisms by which saturated and polyunsaturated fatty acids modulate the function of bacterial and mammalian members of the mechanosensitive ion channel family and develop strategies to ameliorate channel- associated disorders. Furthermore, we will uncover novel physiological roles of the PIEZO subfamily using the animal model C. elegans. Our functional, behavioral, and genetic studies will uncover unifying themes underlying the modulation of mechanosensitive ion channels by membrane composition and reveal novel physiological roles of this family of ion channels.