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CNG channel

Philipp A M Schmidpeter, Xiaolong Gao, Vikrant Uphadyay, Jan Rheinberger, Crina M Nimigean
Cyclic nucleotide-modulated ion channels play several essential physiological roles. They are involved in signal transduction in photoreceptors and olfactory sensory neurons as well as pacemaking activity in the heart and brain. Investigations of the molecular mechanism of their actions, including structural and electrophysiological characterization, are restricted by the availability of stable, purified protein obtained from accessible systems. Here, we establish that SthK, a cyclic nucleotide-gated (CNG) channel from Spirochaeta thermophila , is an excellent model for investigating the gating of eukaryotic CNG channels at the molecular level...
May 11, 2018: Journal of General Physiology
Rong-Chang Li, Chih-Chun Lin, Xiaozhi Ren, Jingjing Sherry Wu, Laurie L Molday, Robert S Molday, King-Wai Yau
In mammalian olfactory transduction, odorants activate a cAMP-mediated signaling pathway that leads to the opening of cyclic nucleotide-gated (CNG), nonselective cation channels and depolarization. The Ca2+ influx through open CNG channels triggers an inward current through Ca2+ -activated Cl channels (ANO2), which is expected to produce signal amplification. However, a study on an Ano2 -/- mouse line reported no elevation in the behavioral threshold of odorant detection compared with wild type (WT). Subsequent studies by others on the same Ano2 -/- line, nonetheless, found subtle defects in olfactory behavior and some abnormal axonal projections from the olfactory receptor neurons (ORNs) to the olfactory bulb...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Zheng Liu, Maro J Kariya, Christopher D Chute, Amy K Pribadi, Sarah G Leinwand, Ada Tong, Kevin P Curran, Neelanjan Bose, Frank C Schroeder, Jagan Srinivasan, Sreekanth H Chalasani
Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation...
March 19, 2018: Nature Communications
Stylianos Michalakis, Elvir Becirovic, Martin Biel
The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration...
March 7, 2018: International Journal of Molecular Sciences
Joachim Täger, Susanne Kohl, David G Birch, Dianna K H Wheaton, Bernd Wissinger, Peggy Reuter
The cyclic nucleotide-gated (CNG) channel - composed of CNGA3 and CNGB3 subunits - mediates the influx of cations in cone photoreceptors after light stimulation and thus is a key element in cone phototransduction. Mutations in CNGA3 and CNGB3 are associated with achromatopsia, a rare autosomal recessive retinal disorder. Here, we demonstrate that the presence of an early nonsense mutation in CNGA3 induces the usage of a downstream alternative translation initiation site giving rise to a short CNGA3 isoform...
February 27, 2018: Experimental Eye Research
Monica Mazzolini, Manuel Arcangeletti, Arin Marchesi, Luisa M R Napolitano, Debora Grosa, Sourav Maity, Claudio Anselmi, Vincent Torre
Cyclic nucleotide-gated (CNG) channels mediate transduction in several sensory neurons. These channels use the free energy of CNs' binding to open the pore, a process referred to as gating. CNG channels belong to the superfamily of voltage-gated channels, where the motion of the α-helix S6 controls gating in most of its members. To date, only the open, cGMP-bound, structure of a CNG channel has been determined at atomic resolution, which is inadequate to determine the molecular events underlying gating. By using electrophysiology, site-directed mutagenesis, chemical modification, and Single Molecule Force Spectroscopy, we demonstrate that opening of CNGA1 channels is initiated by the formation of salt bridges between residues in the C-linker and S5 helix...
January 8, 2018: Scientific Reports
Zachary M James, William N Zagotta
Cyclic nucleotide-binding domain (CNBD) channels are a family of ion channels in the voltage-gated K+ channel superfamily that play crucial roles in many physiological processes. CNBD channels are structurally similar but functionally very diverse. This family includes three subfamilies: (1) the cyclic nucleotide-gated (CNG) channels, which are cation-nonselective, voltage-independent, and cyclic nucleotide-gated; (2) the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are weakly K+ selective, hyperpolarization-activated, and cyclic nucleotide-gated; and (3) the ether-à-go-go -type (KCNH) channels, which are strongly K+ selective, depolarization-activated, and cyclic nucleotide-independent...
February 5, 2018: Journal of General Physiology
Sourav Maity, Nina Ilieva, Alessandro Laio, Vincent Torre, Monica Mazzolini
By combining atomic force microscopy (AFM) imaging and single-molecule force spectroscopy (SMFS), we analyzed membrane proteins of the rod outer segments (OS). With this combined approach we were able to study the membrane proteins in their natural environment. In the plasma membrane we identified native cyclic nucleotide-gated (CNG) channels which are organized in single file strings. We also identified rhodopsin located both in the discs and in the plasma membrane. SMFS reveals strikingly different mechanical properties of rhodopsin unfolding in the two environments...
September 20, 2017: Scientific Reports
Maria Sancho, Eamonn Bradley, Angeles Garcia-Pascual, Domingo Triguero, Keith D Thornbury, Mark A Hollywood, Gerard P Sergeant
Cyclic nucleotide-gated (CNG) channels are non-selective cation channels that mediate influx of extracellular Na(+) and Ca(2+) in various cell types. L-cis-Diltiazem, a CNG channel blocker, inhibits contraction of urethral smooth muscle (USM), however the mechanisms underlying this effect are still unclear. We investigated the possibility that CNG channels contribute to spontaneous pacemaker activity in freshly isolated interstitial cells of Cajal (ICC) isolated from the rabbit urethra (RUICC). Using immunocytochemistry, we found intense CNG1-immunoreactivity in vimentin-immunoreactive RUICC, mainly within patches of the cellular body and processes...
November 5, 2017: European Journal of Pharmacology
Regine Mühlfriedel, Naoyuki Tanimoto, Christian Schön, Vithiyanjali Sothilingam, Marina Garcia Garrido, Susanne C Beck, Gesine Huber, Martin Biel, Mathias W Seeliger, Stylianos Michalakis
Achromatopsia type 2 (ACHM2) is a severe, inherited eye disease caused by mutations in the CNGA3 gene encoding the α subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel. Patients suffer from strongly impaired daylight vision, photophobia, nystagmus, and lack of color discrimination. We have previously shown in the Cnga3 knockout (KO) mouse model of ACHM2 that gene supplementation therapy is effective in rescuing cone function and morphology and delaying cone degeneration. In our preclinical approach, we use recombinant adeno-associated virus (AAV) vector-mediated gene transfer to express the murine Cnga3 gene under control of the mouse blue opsin promoter...
2017: Frontiers in Neuroscience
Michael R Butler, Hongwei Ma, Fan Yang, Joshua Belcher, Yun-Zheng Le, Katsuhiko Mikoshiba, Martin Biel, Stylianos Michalakis, Anthony Iuso, David Križaj, Xi-Qin Ding
Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers...
July 7, 2017: Journal of Biological Chemistry
Zachary M James, Andrew J Borst, Yoni Haitin, Brandon Frenz, Frank DiMaio, William N Zagotta, David Veesler
Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-regulated (HCN) ion channels play crucial physiological roles in phototransduction, olfaction, and cardiac pace making. These channels are characterized by the presence of a carboxyl-terminal cyclic nucleotide-binding domain (CNBD) that connects to the channel pore via a C-linker domain. Although cyclic nucleotide binding has been shown to promote CNG and HCN channel opening, the precise mechanism underlying gating remains poorly understood...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
Tian Wang, Stephen H Tsang, Jeannie Chen
Cyclic-GMP is a second messenger in phototransduction, a G-protein signaling cascade that conveys photon absorption by rhodopsin to a change in current at the rod photoreceptor outer segment plasma membrane. Basal cGMP level is strictly controlled by the opposing actions of phosphodiesterase (PDE6) and retinal guanylyl cyclases (GCs), and mutations in genes that disrupt cGMP homeostasis leads to retinal degeneration in humans through mechanisms that are incompletely understood. The purpose of this study is to examine two distinct cellular targets of cGMP: the cGMP-gated (CNG) channels and protein kinase G (PRKG), and how each may contribute to rod cell death...
June 15, 2017: Human Molecular Genetics
Damien M O'Halloran, Svetlana Altshuler-Keylin, Xiao-Dong Zhang, Chao He, Christopher Morales-Phan, Yawei Yu, Julia A Kaye, Chantal Brueggemann, Tsung-Yu Chen, Noelle D L'Etoile
In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage...
March 13, 2017: Scientific Reports
Tal Einav, Rob Phillips
We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC50 ]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine receptor (nAChR) and the ligand binding domain of a cyclic nucleotide-gated (CNG) ion channel, demonstrating how each mutation can be characterized as only affecting a subset of the biophysical parameters...
April 20, 2017: Journal of Physical Chemistry. B
Stylianos Michalakis, Christian Schön, Elvir Becirovic, Martin Biel
The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide-gated channel...
March 2017: Journal of Gene Medicine
Almke Bader, Willem Bintig, Daniela Begandt, Anne Klett, Ina G Siller, Carola Gregor, Frank Schaarschmidt, Babette Weksler, Ignacio Romero, Pierre-Olivier Couraud, Stefan W Hell, Anaclet Ngezahayo
KEY POINTS: Gap junction channels are essential for the formation and regulation of physiological units in tissues by allowing the lateral cell-to-cell diffusion of ions, metabolites and second messengers. Stimulation of the adenosine receptor subtype A2B increases the gap junction coupling in the human blood-brain barrier endothelial cell line hCMEC/D3. Although the increased gap junction coupling is cAMP-dependent, neither the protein kinase A nor the exchange protein directly activated by cAMP were involved in this increase...
April 15, 2017: Journal of Physiology
Christopher H Ferguson, Haiqing Zhao
In vertebrate olfactory sensory neurons (OSNs), Ca(2+) plays key roles in both mediating and regulating the olfactory response. Ca(2+) enters OSN cilia during the response through the olfactory cyclic nucleotide-gated (CNG) channel and stimulates a depolarizing chloride current by opening the olfactory Ca(2+)-activated chloride channel to amplify the response. Ca(2+) also exerts negative regulation on the olfactory transduction cascade, through mechanisms that include reducing the CNG current by desensitizing the CNG channel via Ca(2+)/calmodulin (CaM), to reduce the response...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Rong-Chang Li, Yair Ben-Chaim, King-Wai Yau, Chih-Chun Lin
Olfactory transduction in vertebrate olfactory receptor neurons (ORNs) involves primarily a cAMP-signaling cascade that leads to the opening of cyclic-nucleotide-gated (CNG), nonselective cation channels. The consequent Ca2+ influx triggers adaptation but also signal amplification, the latter by opening a Ca2+ -activated Cl channel (ANO2) to elicit, unusually, an inward Cl current. Hence the olfactory response has inward CNG and Cl components that are in rapid succession and not easily separable. We report here success in quantitatively separating these two currents with respect to amplitude and time course over a broad range of odorant strengths...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Keisuke Sakurai, Frans Vinberg, Tian Wang, Jeannie Chen, Vladimir J Kefalov
Calcium ions (Ca(2+)) modulate the phototransduction cascade of vertebrate cone photoreceptors to tune gain, inactivation, and light adaptation. In darkness, the continuous current entering the cone outer segment through cGMP-gated (CNG) channels is carried in part by Ca(2+), which is then extruded back to the extracellular space. The mechanism of Ca(2+) extrusion from mammalian cones is not understood. The dominant view has been that the cone-specific isoform of the Na(+)/Ca(2+), K(+) exchanger, NCKX2, is responsible for removing Ca(2+) from their outer segments...
September 1, 2016: Scientific Reports
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