N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide is a newly-designed pain killer selectively activating G-protein-coupled mu-opioid receptors (MOR) in acidic injured tissues, and therefore devoid of central side effects which are typically elicited at normal pH values in healthy tissues. However, the neuronal mechanisms underlying NFEPP's antinociceptive effects were not examined in detail so far. Voltage-dependent Ca channels (VDCCs) in nociceptive neurons play a major role in the generation and inhibition of pain.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
November 2020
TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ.
View Article and Find Full Text PDFTRPM3 proteins assemble to Ca-permeable cation channels in the plasma membrane, which act as nociceptors of noxious heat and mediators of insulin and cytokine release. Here we show that TRPM3 channel activity is strongly dependent on intracellular Ca. Conceivably, this effect is attributed to the Ca binding protein calmodulin, which binds to TRPM3 in a Ca-dependent manner.
View Article and Find Full Text PDFOpioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia.
View Article and Find Full Text PDFBackground And Purpose: Signalling through phospholipase C (PLC) controls many cellular processes. Much information on the relevance of this important pathway has been derived from pharmacological inhibition of the enzymatic activity of PLC. We found that the most frequently employed PLC inhibitor, U73122, activates endogenous ionic currents in widely used cell lines.
View Article and Find Full Text PDFTransient receptor potential A1 channels are well-known as chemosensors in neuronal cells. However, recent studies also point to non-neuronal functions in epithelia. Here, we show that TRPA1 channels are expressed in epithelial MDCK II cells and contribute to Ca(2+) influx and whole-cell currents after stimulation with AITC.
View Article and Find Full Text PDFTRPM3 channels form ionotropic steroid receptors in the plasma membrane of pancreatic β and dorsal root ganglion cells and link steroid hormone signaling to insulin release and pain perception, respectively. We identified and compared the function of a number of TRPM3 splice variants present in mouse, rat and human tissues. We found that variants lacking a region of 18 amino acid residues display neither Ca(2+) entry nor ionic currents when expressed alone.
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