Cyclic Nucleotide-Gated Ion Channels

Matulef, Kimberly; Zagotta, William N.

doi:10.1146/annurev.cellbio.19.110701.154854

Cited by 208 publications

(183 citation statements)

References 142 publications

Supporting

Mentioning

180

Contrasting

Order By: Relevance

“…Our previous results and work from other investigators suggest that ENaC gating is regulated in an allosteric manner by extracellular cues (5,9,11). These observations raise the possibility that ENaC is a ligand-gated channel, similar to ATP-sensitive inward rectifier K ϩ channels (K ATP ) (35), cyclic nucleotide-gated channels (36), and glutamate receptor ion channels (37). Extracellular Na ϩ would serve as a ligand whose binding to ENaC reduces channel open probability, and Zn 2ϩ prevents or reverses Na ϩ self-inhibition as a potential physiological regulator or ligand.…”

Section: External Zn 2ϩ Activates ␣␤␥ Menac Expressed In Xenopusmentioning

confidence: 55%

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

Sheng

Perry

Kleyman

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Inhibition of epithelial Na ؉ channel (ENaC) activity by high concentrations of extracellular Na ؉ is referred to as Na ؉ self-inhibition. We investigated the effects of external Zn 2؉ on whole cell Na ؉ currents and on the Na ؉ self-inhibition response in Xenopus oocytes expressing mouse ␣␤␥ ENaC. Na ؉ self-inhibition was examined by analyzing inward current decay from a peak current to a steady-state current following a fast switching of a low Na ؉ (1 mM) bath solution to a high Na ؉ (110 mM) solution. Our results indicate that external Zn 2؉ rapidly and reversibly activates ENaC in a dose-dependent manner with an estimated EC 50 of 2 M. External Zn 2؉ in the high Na ؉ bath also prevents or reverses Na ؉ self-inhibition with similar affinity. Zn 2؉ activation is dependent on extracellular Na ؉ concentration and is absent in ENaCs containing ␥H239 mutations that eliminate Na ؉ self-inhibition and in ␣S580C␤␥ following covalent modification by a sulfhydryl-reactive reagent that locks the channels in a fully open state. In contrast, external Ni 2؉ inhibition of ENaC currents appears to be additive to Na ؉ self-inhibition when Ni 2؉ is present in the high Na ؉ bath. Pretreatment of oocytes with Ni 2؉ in a low Na ؉ bath also prevents the current decay following a switch to a high Na ؉ bath but rendered the currents below the control steady-state level measured in the absence of Ni 2؉ pretreatment. Our results suggest that external Zn 2؉ activates ENaC by relieving the channel from Na ؉ self-inhibition, and that external Ni 2؉ mimics or masks Na ؉ self-inhibition.

show abstract

Section: External Zn 2ϩ Activates ␣␤␥ Menac Expressed In Xenopusmentioning

confidence: 55%

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

Sheng

Perry

Kleyman

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Induced cAMP levels are reduced in FX and all three models have deficient stimulated cAMP production. This study suggests that neurotransmitters and receptors signaling through cAMP would be functionally deficient in FX as would the influence of cAMP on cAMP-gated channels, GEFs, and EPAC signaling (Lauder 1993;Neves, Ram et al 2002;Matulef and Zagotta 2003). If cAMP induction is reduced across neural cell types, all members of the tripartite synapse (Araque, Parpura et al 1999) could be compromised with respect to cAMP signaling.…”

Section: Cyclic Amp Theory Of Fragile Xmentioning

confidence: 89%

“…One known cAMP function is to serve as a second messenger that can activate cAMP-dependent PKA, an enzyme that phosphorylates tertiary messengers, which themselves can signal subsequent messengers. Alternatively cAMP can act directly as a transmitter by binding cyclic nucleotide gated channels (Matulef and Zagotta 2003). Cyclic AMP produces short term or long term changes in neuron function by acting respectively through PKA or an EPAC-Rap-MAPK cascade involving an exchange protein activated by cAMP (EPAC), a small GTPase (Rap1), and a mitogen-activated protein kinase (MAPK) (Neves, Ram et al 2002).…”

Section: Cyclic Amp Cascadementioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

View full text Add to dashboard Cite

Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

show abstract

“…Our findings reported here are a successful attempt of studying CBD-A of the R-subunit by multidimensional solution NMR methods. Furthermore, the proposed model defines a mechanism that is highly conserved and thus relevant for cAMP recognition in other homologous CBDs coupled to effector proteins with diverse functions, such as transcription factors (catabolite-activator protein) (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), guanine nucleotide exchange factors (11), and ion channel proteins (both hyperpolarization-activated cyclic nucleotide-dependent channels and cyclic nucleotide-gated channels) (32,33). This model also serves as a general paradigm for how small molecules such as cAMP allosterically control large proteinprotein interfaces.…”

mentioning

confidence: 99%

cAMP activation of PKA defines an ancient signaling mechanism

Das

Esposito

Abu-Abed

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

117

106

View full text Add to dashboard Cite

allostery ͉ NMR ͉ cyclic nucleotide binding domain T he cAMP binding domain (CBD) and cAMP are conserved from bacteria to humans as a ubiquitous signaling mechanism to translate extracellular stress signals into appropriate biological responses (1). The major receptor for cAMP in higher eukaryotes, cAMP-dependent PKA (2), is ubiquitous in mammalian cells where it exists in two forms: the inactive tetrameric holoenzyme and the active dissociated catalytic subunit (Csubunit). In the inactive holoenzyme, two C-subunits are bound to a dimeric regulatory subunit (R-subunit) (Fig. 1a). Upon binding cAMP, the R-subunits undergo a conformational change that unleashes the active C-subunits (3, 4). The Rsubunits are composed of an N-terminal dimerization/docking domain, a flexible linker that includes an autoinhibitory segment, and two tandem CBDs (CBD-A and CBD-B; Fig. 1b) (5). The CBD-A of the isoform I␣ of the R-subunit of PKA (RI␣) contains a noncontiguous ␣-subdomain, which mediates the interactions with the C-subunit and a contiguous ␤-subdomain that forms a ␤-sandwich and contains the cAMP binding pocket (i.e., the phosphate binding cassette or PBC) ( Fig. 1 c and d) (6).Crystal structures of CBD-A of RI␣ in its cAMP-(6) and C-bound (7) states have revealed two very different conformations, highlighting the conformational plasticity of this ancient domain. Although these static crystal structures define two stable end points, questions remain about the allosteric control of the reversible shuttling between the two states. How does the signal generated by cAMP binding to the PBC (Fig. 1 c and d) propagate through a long-range allosteric network that spans both ␣-and ␤-subdomains? Previous analyses (8-16) have led to the proposal of an initial allosteric model in which the ␣-and ␤-subdomains are directly coupled to each other through a salt bridge between E200 and R241 and also possibly through a hydrophobic hinge defined by the L203, I204, and Y229 side-chain cluster (9,11,12). However, mutations (17), sequence conservation analyses (1), structurebased comparisons (1), and genetic screening (18,19) indicate that several other sites, which are not accounted for by the existing model, are also likely to play an active role in the cAMP-mediated activation of PKA. To comprehensively understand this allosteric mechanism, it is therefore necessary to elucidate at high resolution how cAMP remodels the free energy landscape of CBD-A, which serves as the central controlling unit of PKA. For this purpose, we have investigated by NMR RI␣ (residues 119-244), a construct that spans both ␣-and ␤-subdomains of CBD-A and retains high-

show abstract

Cyclic Nucleotide-Gated Ion Channels

Cited by 208 publications

References 142 publications

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

The cyclic AMP phenotype of fragile X and autism

cAMP activation of PKA defines an ancient signaling mechanism

Contact Info

Product

Resources

About