Monoamine

Alexander, S P H; Mathie, A; Peters, J A

doi:10.1038/sj.bjp.0706489

Cited by 5 publications

(7 citation statements)

References 9 publications

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“…To establish that heteromeric transfected cells expressed heteromers, the well described calcium permeability of homomeric ASIC-1 channels was exploited (37)(38)(39)(40). In our hands, when external sodium was replaced with the impermeant cation N-methyl-D-glucamine and the only major cation gradients were for calcium influx and potassium efflux, homomeric hASIC-1b-transfected cells showed a significant acid-induced inward current of ϳ63.3% of the peak current as compared with conditions with sodium at pH 5.0 (Fig.…”

Section: Experimental Tests Of the Modelmentioning

confidence: 99%

Psalmotoxin-1 Docking to Human Acid-sensing Ion Channel-1

Qadri¹,

Berdiev²,

Song

et al. 2009

Journal of Biological Chemistry

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Acid-sensing ion channel-1 (ASIC-1) is a proton-gated ion channel implicated in nociception and neuronal death during ischemia. Recently the first crystal structure of a chicken ASIC was obtained. Expanding upon this work, homology models of the human ASICs were constructed and evaluated. Energy-minimized structures were tested for validity by in silico docking of the models to psalmotoxin-1, which potently inhibits ASIC-1 and not other members of the family. The data are consistent with prior radioligand binding and functional assays while also explaining the selectivity of PcTX-1 for homomeric hASIC-1a. Binding energy calculations suggest that the toxin and channel create a complex that is more stable than the channel alone. The binding is dominated by the coulombic contributions, which account for why the toxin-channel interaction is not observed at low pH. The computational data were experimentally verified with single channel and whole-cell electrophysiological studies. These validated models should allow for the rational design of specific and potent peptidomimetic compounds that may be useful for the treatment of pain or ischemic stroke.Acid-sensing ion channels are a subfamily of the epithelial sodium channel/degenerin family of proteins (1). The proteins in this family share a general topology; each member has two transmembrane-spanning domains, relatively short intracellular N and C termini, and a large extracellular loop containing multiple cysteine-rich domains. These proteins interact with themselves and other family members to form ion channels with unique properties (1, 2). The channels formed are all functionally linked by sensitivity to the small molecule inhibitor amiloride and a general selectivity for conducting sodium despite a sequence identity ranging from 15 to 60% across the family. The epithelial sodium channel/degenerin proteins are important for many physiological and pathophysiological processes. For example, ␣␤␥-epithelial sodium channel channels expressed in the kidney are important in blood pressure homeostasis, whereas homomeric ASIC-1 channels found in neurons are implicated in nociception and neuronal death during ischemia (1, 3).Using fluorescence detection size exclusion chromatography, Jasti et al. (4) found that homomeric chicken acid-sensing ion channel-1 (ASIC-1) 2 could be crystallized and described the structure of a homomeric cASIC-1 channel lacking intracellular domains and in a nonfunctional state. Unfortunately chicken ASICs are very poorly characterized either pharmacologically or functionally. As crystallization of integral membrane proteins is a challenging technique, obtaining crystal structures of the human members of this family may not be feasible. Despite species difference of just a few amino acids, there may be clinically relevant variations between ASIC homologs (5).This work used homology modeling to deduce structures of the human ASICs. These models were evaluated using structural verification suites and validated using in silico inhibitor docking to r...

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Section: Experimental Tests Of the Modelmentioning

confidence: 99%

Psalmotoxin-1 Docking to Human Acid-sensing Ion Channel-1

Qadri¹,

Berdiev²,

Song

et al. 2009

Journal of Biological Chemistry

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“…In some somatic cells, adenosine activates cell surface G-protein-coupled adenosine receptors that couple to various conventional transmembrane adenylyl cyclases (ADCY1-9) to control synthesis of cAMP (12,13). However, in sperm the predominant (perhaps the only) adenylyl cyclase is the atypical SACY (ADCY10) (8), which lacks transmembrane domains and is unaffected by G-proteins (14,15).…”

mentioning

confidence: 99%

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

Burnett¹,

Blais²,

Unadkat

et al. 2010

Journal of Biological Chemistry

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Adenosine is a candidate modulator of sperm motility in the female reproductive tract that increases sperm flagellar beat frequency in vitro. Past work suggested that this acceleration may involve equilibrative (ENT) and concentrative (CNT) nucleoside transporters. Here we show that Slc29a1 (ENT-1) is the predominant nucleoside transporter expressed in the mouse testis. Unexpectedly, the beat of Slc29a1-null sperm still accelerates in response to 2-chloro-2-deoxyadenosine (Cl-dAdo). The only known roles of sperm are to reach the egg and deliver its genetic payload and to initiate early signaling events in the zygote. Although the list is short, the tasks are complex, and the sperm requires numerous specialized components to accomplish these goals. Our recent work has focused on how the sperm applies its specialized components to control swimming behavior. We have combined biophysical methods with a genetic approach, using sperm from null-mutant (knock-out) mice that carry targeted disruptions of the genes for several of the components of the signaling pathways that operate in the sperm flagellum. This approach has provided definitive evidence for required roles of the unique CatSper ion channel proteins (1-7), for the atypical sperm adenylyl cyclase SACY 2

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“…The current database of receptors and their corresponding genes can be seen in the 2008 paper by Alexander et al 23 The concept in the early days was demonstrated by Ahlquist 3 and then "defined" by Black et al 6,7 This concept implied that if there are activators (agonists) then there will be inactivators (antagonists), if they can be discovered.…”

Section: Beta-antagonistsmentioning

confidence: 99%

“…23 They are located primarily in the small intestine, adipose tissue and vascular endothelium. Here they are involved in lipolysis, glucose uptake, cardio-inhibition and relaxation of colon, esophagus and bladder.…”

Section: β-Agonistsmentioning

confidence: 99%

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

Newman¹

2016

Journal of the Brazilian Chemical Society

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This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) that would not have been synthesized in the absence of knowledge of bioactive arabinose nucleosides.

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Monoamine

Cited by 5 publications

References 9 publications

Psalmotoxin-1 Docking to Human Acid-sensing Ion Channel-1

Psalmotoxin-1 Docking to Human Acid-sensing Ion Channel-1

Testicular Expression of Adora3i2 in Adora3 Knockout Mice Reveals a Role of Mouse A3Ri2 and Human A3Ri3 Adenosine Receptors in Sperm*

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

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