Sensory Ion Channel Modulation by Bioactive Lipids

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Our current research focuses on investigating the mechanisms by which bioactive lipids modulate the function of vascular and sensory transient receptor potential (TRP) ion channels. Members of the TRP ion channel subfamily are involved in various physiological processes, including temperature, chemical, and noxious stimuli detection, as well as osmoregulation and neuronal and vascular function. TRP channel dysfunction underlies different pathophysiological conditions such as pain hypersensitivity, peripheral neuropathies (e.g., during diabetes), inflammation, hypertension, neurological disorders (e.g., cerebellar ataxia), and kidney disease. Since TRP channels play critical roles in health and disease, there are many challenges that agonists and antagonists must overcome during clinical trials due to their side effects. We envision that new strategies that fine-tune TRP channels function, while maintaining their physiological roles, might circumvent undesired side effects of pharmaceutical drugs. In the past five years, we have gained insights into the mechanisms by which polyunsaturated fatty acids (PUFAs), phosphoinositide lipids, and diacylglycerol regulate the function of TRPV4, TRPV1, and TRPC6, respectively. Combining various in vitro and in vivo approaches, we aim to depict the mechanism by which ω-3 PUFAs increase TRPV4 function and its potential for ameliorating channel-mediated vascular dysfunction. Moreover, we will focus on determining the structural bases of the TRPV1 C-terminal domain interaction with the plasma membrane and the intrinsic sensitivity of TRPC channels to bioactive lipids. Taken together, our proposed work is expected to provide the molecular framework for understanding how bioactive lipids fine-tune TRP channel function in the vascular and nervous systems. These findings will, in turn, facilitate the development of strategies to target TRP channels, without disrupting normal physiology.