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Paving the way for designing drugs targeting TMEM16A
Full text linkThe calcium-activated chloride channel TMEM16A is involved in several physiological processes and is an important pharmacological target. Dinsdale and colleagues recently unveiled several residues in the outer pore region that constitute a critical site for the design of drugs that modulate TMEM16A channels
Permeation Mechanisms in the TMEM16B Calcium-Activated Chloride Channels.
Full text linkTMEM16A and TMEM16B encode for Ca2+-activated Cl- channels (CaCC) and are expressed in many cell types and play a relevant role in many physiological processes. Here, I performed a site-directed mutagenesis study to understand the molecular mechanisms of ion permeation of TMEM16B. I mutated two positive charged residues R573 and K540, respectively located at the entrance and inside the putative channel pore and I measured the properties of wild-type and mutant TMEM16B channels expressed in HEK-293 cells using whole-cell and excised inside-out patch clamp experiments. I found evidence that R573 and K540 control the ion permeability of TMEM16B depending both on which side of the membrane the ion substitution occurs and on the level of channel activation. Moreover, these residues contribute to control blockage or activation by permeant anions. Finally, R573 mutation abolishes the anomalous mole fraction effect observed in the presence of a permeable anion and it alters the apparent Ca2+-sensitivity of the channel. These findings indicate that residues facing the putative channel pore are responsible both for controlling the ion selectivity and the gating of the channel, providing an initial understanding of molecular mechanism of ion permeation in TMEM16B
Anoctamin 2/TMEM16B: A calcium-activated chloride channel in olfactory transduction
Full text linkIn vertebrate olfactory transduction, a Ca2+-dependent Cl- efflux greatly amplifies the odorant response. The binding of odorants to receptors in the cilia of olfactory sensory neurons activates a transduction cascade that involves the opening of cyclic nucleotide-gated channels and the entry of Ca2+ into the cilia. The Ca2+ activates a Cl- current that, in the presence of a maintained elevated intracellular Cl- concentration, produces an efflux of Cl- ions and amplifies the depolarization. In this review, we summarize evidence supporting the hypothesis that anoctamin 2/TMEM16B is the main, or perhaps the only, constituent of the Ca2+-activated Cl- channels involved in olfactory transduction. Indeed, studies from several laboratories have shown that anoctamin 2/TMEM16B is expressed in the ciliary layer of the olfactory epithelium, that there are remarkable functional similarities between currents in olfactory sensory neurons and in HEK 293 cells transfected with anoctamin 2/TMEM16B, and that knockout mice for anoctamin 2/TMEM16B did not show any detectable Ca2+-activated Cl- current. Finally, we discuss the involvement of Ca2+-activated Cl- channels in the transduction process of vomeronasal sensory neurons and the physiological role of these channels in olfaction. © 2011 The Authors. Experimental Physiology © 2012 The Physiological Society
Antibiotic prophylaxis can lead to contamination with Clostridium difficile - Reply
No full textAuthors' replyEDITOR---Unlike Sanderson, we find it interesting rather than ironic that our review was in the same issue of the House of Lords' report that was aimed at stimulating critical thinking against generalised fears of antimicrobial resistance. Critically ill patients undergoing ventilation are at high risk of pneumonia and death, and the issue whether or not they should be routinely treated with antimicrobials deserves great attention.We accessed data on individual patients, which allowed us to ascertain that most patients in all trials were treated with antimicrobials at some point during their stay in an intensive care unit, regardless of the initial policy of the unit. The question is thus no longer whether, but rather when, they should be treated---immediately, as a policy, or only once their infection becomes clinically evident
Signal transduction in vertebrate olfactory Cilia
No full textThe initial steps of olfaction occur in primary sensory neurons located in the olfactory epithelium of the nasal cavity of vertebrates. These neurons are responsible for the detection of odorant molecules present in the surrounding environment and the generation of the neural signal that is transmitted to the brain. The morphology of the primary sensory neurons was described by Max Schultze in the second half of the nineteenth century (for review, see Zippel 1993), but only about 100 years later the first reviews describing some functional properties of these neurons were published (Getchell 1986; Lancet 1986). Primary sensory neurons of the olfactory epithelium, often indicated by various names: olfactory receptor cells (ORCs), olfactory sensory neurons (OSNs), or olfactory receptor neurons (ORNs), are bipolar neurons with a single dendrite that terminates with a knob, from which several tiny cilia protrude, where the transduction of the olfactory signal takes place. Odorant molecules bind to odorant receptors, and this interaction triggers an increase in the intraciliary concentration of cyclic adenosine monophosphate (cAMP) through the activation of the receptor-coupled G-protein and adenylyl cyclase (AC). Cyclic nucleotide-gated (CNG) channels located in the ciliary membrane are directly activated by cytoplasmic cAMP, causing a depolarizing influx of Na+ and Ca+ ions. The odorant-induced inward transduction current has been shown to be composed not only of a cation influx through CNG channels, but also of a Cl efflux through Cl channels activated by Ca2+ (Cl(Ca) channels). This chapter will review the molecular mechanisms underlying the functional role of vertebrate olfactory cilia
Ca2+-Activated Chloride Channels and Phospholipid Scramblases
Full text link: The functional characterization of the TMEM16 protein family unexpectedly brought together two different research fields in membrane biology: anion channel and membrane lipid organization [...]
Anion and cation permeability of the mouse tmem16f calcium-activated channel
Full text linkTMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca2+-dependent phospholipid scram-blase and a Ca2+-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca2+-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na+ and Cl ̄ (PNa /PCl ) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, PNa /PCl was approximately 0.5, indicating a slight preference for Cl ̄ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na+ with PNa /PCl reaching 3.7. Our results demonstrate that the time dependence of Ca2+ activation and the ion selectivity of TMEM16F depend on the recording configuration
New whiffs about chemesthesis. Focus on "TRPM5-expressing solitary chemosensory cells respond to odorous irritants"
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