scholarly journals Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Elvir Becirovic ◽  
Martin Biel ◽  
Stefanie Fenske ◽  
Verena Hammelmann ◽  
Franz Hofmann ◽  
...  
Keyword(s):  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cardiac Cells ◽  
Cation Channels ◽  
Sensory Cells ◽  
Hcn Channels ◽  
C Terminus ◽  
Olfactory Systems ◽  
Voltage Gated Ion Channels

Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [83, 120], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [181] and the pineal gland [71]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.The HCN channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [64, 192]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [139, 146, 140]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR Subcommittee on voltage-gated ion channels [108].

scholarly journals Cyclic nucleotide-regulated channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Elvir Becirovic ◽  
Martin Biel ◽  
Verena Hammelmann ◽  
Franz Hofmann ◽  
U. Benjamin Kaupp
Keyword(s):  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cardiac Cells ◽  
Cation Channels ◽  
Sensory Cells ◽  
Hcn Channels ◽  
Excitable Cells ◽  
C Terminus ◽  
Voltage Gated Ion Channels

Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [69, 98], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [153] and the pineal gland [60]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [56, 164]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [117, 121]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [88].

scholarly journals Growth hormone, cyclic nucleotides and the rapid control of translation in heart muscle

1975 ◽  
Vol 152 (3) ◽  
pp. 583-592 ◽  
Author(s):  
J Mowbray ◽  
J A Davies ◽  
D J Bates ◽  
C J Jones
Keyword(s):  
Growth Hormone ◽  
Protein Synthesis ◽  
Cyclic Amp ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Precursor Pool ◽  
Growth Hormone Action ◽  
Constant Rate ◽  
The Individual

Perfused rat heart incorporated L-[14C]tyrosine into protein at a constant rate for up to 75 min. A purified bovine growth-hormone preparation (1 mug/ml) stimulated the incorporation to a new constant rate that was more than three times the control rate by 10 min after hormone addition to perfusate. The hormone, however, did not alter the intracellular tracer amino acid pool, and the relationship of this to the aminoacyl-tRNA precursor pool is discussed. It is concluded that the increased incorporation largely reflected a rapid increase in protein synthesis at the ribosomes. Measurements of cyclic nucleotide contents during the perfusion showed that these appeared to vary in a systematic way during the perfusion. This strands in contrast with the constant values given by several other parameters measured in this preparation. Futher, the cyclic nucleotide variation seems to be independent of external effectors. The steady-state performance of the heart correlates more closely the [cyclic AMP]/[cyclic GMP] ratio than with the content of the individual cyclic nucleotides. At 10 min after the addition of growth hormone a slight decrese in cyclic AMP content and a large decrease in cyclic GMP were found, suggesting that the hormone's effect in stimulating protein synthesis may be mediated by a decrease in cyclic nucleotide concentrations or an increase in the [cyclic AMP]/[cyclic |p] ratio. The findings are also consistent with an intracellularly directed role for these nucleotides, and the possibility that the cyclic nucleotide changes are an indirect result of growth-hormone action is discussed.

scholarly journals Immunofluorescent localization of cyclic nucleotide-dependent protein kinases on the mitotic apparatus of cultured cells.

1980 ◽  
Vol 87 (2) ◽  
pp. 336-345 ◽  
Author(s):  
C L Browne ◽  
A H Lockwood ◽  
J L Su ◽  
J A Beavo ◽  
A L Steiner
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Kinases ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Mitotic Spindle ◽  
Cyclic Nucleotide ◽  
Dependent Protein Kinase ◽  
Mitotic Apparatus ◽  
Dependent Protein

Cyclic nucleotides and cyclic nucleotide-dependent protein kinases have been implicated in the regulation of cell motility and division, processes that depend on the cell cytoskeleton. To determine whether cyclic nucleotides or their kinases are physically associated with the cytoskeleton during cell division, fluorescently labeled antibodies directed against cyclic AMP, cyclic GMP, and the cyclic nucleotide-dpendent protein kinases were used to localize these molecules in mitotic PtK1 cells. Both the cyclic GMP-dependent protein kinase and the type II regulatory subunit of the cyclic AMP-dependent protein kinase were localized on the mitotic spindle. Throughout mitosis, their distribution closely resembled that of tubulin. Antibodies to cyclic AMP, cyclic GMP, and the type I regulatory and catalytic subunits of the cyclic AMP-dependent protein kinase did not label the mitotic apparatus. The association between specific components of the cyclic neucleotide system and the mitotic spindle suggests that cyclic nucleotide-dependent phosphorylation of spindle proteins, such as those of microtubules, may play a fundamental role in the regulation of spindle assembly and chromosome motion.

scholarly journals Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels

2017 ◽  
Vol 292 (43) ◽  
pp. 17718-17730 ◽  
Author(s):  
Kyle A. Lyman ◽  
Ye Han ◽  
Robert J. Heuermann ◽  
Xiangying Cheng ◽  
Jonathan E. Kurz ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cyclic Nucleotide ◽  
Tetratricopeptide Repeat ◽  
Hcn Channels ◽  
Protein Protein Interactions ◽  
C Terminus ◽  
Peroxisomal Targeting ◽  
Targeting Signal ◽  
Peroxisomal Targeting Signal

Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein–protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal motifs. A homolog of PEX5, tetratricopeptide repeat–containing Rab8b-interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide (HCN)–gated channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity. In this report, we found that the cyclic nucleotide–binding domain and the C terminus of the HCN channel are critical for conferring specificity to TRIP8b binding. We show that TRIP8b binds the HCN cyclic nucleotide–binding domain through a 37-residue domain and the HCN C terminus through the TPR domains. Using a combination of fluorescence polarization– and co-immunoprecipitation–based assays, we establish that binding at either site increases affinity at the other. Thus, allosteric coupling of the TRIP8b TPR domains both promotes binding to HCN channels and limits binding to type 1 peroxisomal targeting signal substrates. These results raise the possibility that other TPR domains may be similarly influenced by allosteric mechanisms as a general feature of protein–protein interactions.

scholarly journals Light-induced dephosphorylation of two proteins in frog rod outer segments: influence of cyclic nucleotides and calcium.

1979 ◽  
Vol 74 (5) ◽  
pp. 595-613 ◽  
Author(s):  
A S Polans ◽  
J Hermolin ◽  
M D Bownds
Keyword(s):  
Cyclic Amp ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Outer Segment ◽  
Intermediate Level ◽  
Continuous Illumination ◽  
Rod Outer Segments ◽  
Pharmacological Agents ◽  
Outer Segments

Two minor proteins of frog rod outer segments become phosphorylated when retinas are incubated in the dark with 32Pi. The proteins, designated component I (13,000 daltons) and component II (12,000 daltons), are dephosphorylated when retinas are illuminated. The dephosphorylation is reversible; the two proteins are rephosphorylated when illumination ceases. Each outer segment contains approximately 10(6( molecules of components I and II. These remain associated with both fragmented and intact outer segments but dissociate from the outer segment membranes under hypoosmotic conditions. The extent of the light-induced dephosphorylation increases with higher intensities of illumination and is maximal with continuous illumination which bleaches 5.0 x 10(5) rhodopsin molecules/outer segment per second. Light which bleaches 5.0 x 10(3) rhodopsin molecules/outer segment per second causes approximately half-maximal dephosphorylation. This same intermediate level of illumination causes half-suppression of the light-sensitive permeability mechanism in isolated outer segments (Brodie and Bownds. 1976. J. Gen Physiol. 68:1-11) and also induces a half-maximal decrease in their cyclic GMP content (Woodruff et al. 1977. J. Gen. Physiol. 69:667-679). The phosphorylation of components I and II is enhanced by the addition of cyclic GMP or cyclic AMP to either retinas or isolated rod outer segments maintained in the dark. Several pharmacological agents which influence cyclic GMP levels in outer segments, including calcium, cause similar effects on the phosphorylation of components I and II and outer segment permeability. Although the cyclic nucleotide-stimulated phosphorylation can be observed either in retinas or isolated rod outer segments, the light-induced dephosphorylation is observed only in intact retinas.

Radioimmunoassay for adenosine 3', 5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate in human blood, urine, and cerebrospinal fluid.

1977 ◽  
Vol 23 (3) ◽  
pp. 576-580 ◽  
Author(s):  
M L Goldberg
Keyword(s):  
Cerebrospinal Fluid ◽  
Cyclic Amp ◽  
Human Blood ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cyclic Monophosphate ◽  
Specificity And Sensitivity ◽  
Analytical Recovery ◽  
Highly Sensitive

Abstract I describe a highly sensitive and very specific assay for cyclic AMP and cyclic GMP in body fluids. An adaptation of the method of Harper and Brooker [j. cyclic Nucleotide Res. 1,207 (1975)], its advantage lies in the fact that the simple acetylation of the samples--a procedure developed by these workers--greatly increases specificity and sensitivity beyond those of previous methods and permits the measurement of femtomole quantities of both cyclic nucleotides without prepurification. Because the range of the cyclic AMP assay is 20-200 fmol, and that of cyclic GMP 10-15 fmol, experiments can be performed with use of only microliters of fluid. The method requires no extraction and thus no complicated corrections are necessary for analytical recovery.

scholarly journals Visualization of cyclic nucleotide binding sites in the vertebrate retina by fluorescence microscopy.

1989 ◽  
Vol 108 (4) ◽  
pp. 1517-1522 ◽  
Author(s):  
A Caretta ◽  
H Saibil
Keyword(s):  
Plasma Membrane ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Binding Sites ◽  
Specific Binding ◽  
Cation Channels ◽  
Retinal Layer ◽  
Vertebrate Retina ◽  
Wide Range ◽  
Sites Of Action

Cyclic nucleotides play a major role in cell signaling, especially in the nervous system. They act as cytoplasmic messengers in a wide range of physiological responses, but the spatial distribution of their sites of action within cells and tissues is not well-known. In the vertebrate retina, there is a class of well-characterized cGMP binding sites which control the permeability of cation channels in the rod outer segments (ROS), while cAMP is involved in several other systems in the inner retina. Biochemical studies of the cGMP-activated permeability in ROS have not distinguished between the subcellular compartments of disk and plasma membrane. By a new method using fluorescein-conjugated cyclic nucleotides, we have found strong cyclic GMP binding to the plasma membrane of the ROS, both on frozen sections of retina and in freshly isolated, leaky ROS. We also found a high density of cGMP binding sites on structures resembling the inner segment calycal processes. Little specific binding could be detected on the disk membranes or on any other retinal layer. In contrast, fluorescent cAMP did not label ROS, but gave a striking pattern of labeling on several deeper layers of the retina. These results suggest that the ROS plasma membrane has a much higher density of cGMP-controlled cation channels than the disk membranes, and point to other retinal layers where cAMP is likely to shape cellular responses. This method opens up novel morphological approaches to the study of cyclic nucleotide regulation.

scholarly journals The Complex Story of Plant Cyclic Nucleotide-Gated Channels

2021 ◽  
Vol 22 (2) ◽  
pp. 874
Author(s):  
Edwin Jarratt-Barnham ◽  
Limin Wang ◽  
Youzheng Ning ◽  
Julia M. Davies
Keyword(s):  
Arabidopsis Thaliana ◽  
Stress Response ◽  
Complex Formation ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cation Channels ◽  
Cyclic Monophosphate ◽  
Cyclic Nucleotide Gated Channels ◽  
Gated Channel

Plant cyclic nucleotide-gated channels (CNGCs) are tetrameric cation channels which may be activated by the cyclic nucleotides (cNMPs) adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). The genome of Arabidopsis thaliana encodes 20 CNGC subunits associated with aspects of development, stress response and immunity. Recently, it has been demonstrated that CNGC subunits form heterotetrameric complexes which behave differently from the homotetramers produced by their constituent subunits. These findings have widespread implications for future signalling research and may help explain how specificity can be achieved by CNGCs that are known to act in disparate pathways. Regulation of complex formation may involve cyclic nucleotide-gated channel-like proteins.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders

2020 ◽  
Vol 60 (1) ◽  
pp. 109-131 ◽  
Author(s):  
Bina Santoro ◽  
Mala M. Shah
Keyword(s):  
Neuronal Activity ◽  
Cyclic Nucleotide ◽  
Neurological Disorders ◽  
Drug Targets ◽  
Neuronal Excitability ◽  
Current Knowledge ◽  
Hcn Channels ◽  
Voltage Gated Ion Channels ◽  
The Individual ◽  
And Function

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits ( HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.

scholarly journals Binding and structural asymmetry governs ligand sensitivity in a cyclic nucleotide–gated ion channel

2019 ◽  
Vol 151 (10) ◽  
pp. 1190-1212 ◽  
Author(s):  
Leo C.T. Ng ◽  
Meiying Zhuang ◽  
Filip Van Petegem ◽  
Yue Xian Li ◽  
Eric A. Accili
Keyword(s):  
Binding Site ◽  
Cyclic Nucleotide ◽  
Single Point ◽  
Titration Calorimetry ◽  
Hcn Channels ◽  
Negative Cooperativity ◽  
Response Data ◽  
C Terminus ◽  
Channel Opening ◽  
Ligand Sensitivity

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open more easily when cAMP or cGMP bind to a domain in the intracellular C-terminus in each of four identical subunits. How sensitivity of the channels to these ligands is determined is not well understood. Here, we apply a mathematical model, which incorporates negative cooperativity, to gating and mutagenesis data available in the literature and combine the results with binding data collected using isothermal titration calorimetry. This model recapitulates the concentration–response data for the effects of cAMP and cGMP on wild-type HCN2 channel opening and, remarkably, predicts the concentration–response data for a subset of mutants with single-point amino acid substitutions in the binding site. Our results suggest that ligand sensitivity is determined by negative cooperativity and asymmetric effects on structure and channel opening, which are tuned by ligand-specific interactions and residues within the binding site.

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