EAI045 Will Highlight Beginner Tactics . . . Our Staff Members Head Into The Concept

Indeed, a fluorescent version of Opi1 demonstrates that, when the GUCY1B3 pH of the cell drops, Opi1 dissociates from the phosphatidic acid and travels to the nucleus to repress lipid synthesis genes. How does phosphatidic acid sense pH, and what physiological role does it serve? Glucose starvation triggers a rapid drop in intracellular pH from 7 to ?6.0. The phosphate group of phosphatidic acid is unique among phospholipids in that it is negatively charged at pH 7 but neutral at pH EAI045 research buy this type of pH biosensor is probably a common signaling mechanism for coupling a physiological state to membrane biogenesis. Young et?al. (2010). Science 329, 1085�C1088. Phosphatidic acid (PA) serves as a pH sensor in yeast, linking glucose availability to membrane biogenesis through its interaction with the transcriptional repressor Opi1. Image courtesy of C.?Loewen. Whereas phosphatidic acid is a key signaling lipid inside of cells, many lipids can also transmit information between cells. One potent class of these ��lipid messengers�� is endocannabinoids, such anandamide. Neurons secrete anandamide, which then blocks pain perception by activating cannabinoid receptors in both the central and peripheral nervous systems. Now, Clapper et?al. (2010) develop a small molecule that boosts anandamide levels in the peripheral nervous system, but not in the brain or spinal cord. Despite its restricted range of action, this molecule exhibits surprisingly powerful analgesic effects in mice models of acute and chronic pain, opening a new avenue for treating pain without unwanted psychotropic effects. Anandamide is degraded by a membrane protein called fatty acid amide hydrolase, or FAAH. Current inhibitors of FAAH raise anandamide concentrations but are quite hydrophobic and thus easily cross the blood-brain barrier. To create FAAH inhibitors that act only in the periphery, Clapper et?al. add hydrophilic groups at sites unlikely to alter interactions with FAAH. One molecule, called URB937, increases anandamide levels in peripheral Selleckchem A-1331852 tissues, but not in the forebrain or hypothalamus. Most importantly, administration of this compound near damaged tissue reduces pain responses in mice with efficacies comparable to centrally acting FAAH inhibitors and a common nonsteroidal anti-inflammatory compound. These results suggest that amplifying endocannabinoid levels in the peripheral nervous system alters the processing of pain signals in the spinal cord, highlighting the potency of these lipid-based neuromodulators throughout the body. Clapper et?al. (2010).