Pharmacological characterization of the Haemonchus contortus GABA-gated chloride channel, Hco-UNC-49: Modulation by macrocyclic lactone anthelmintics and a receptor for piperazine

Brown, David D. R.; Siddiqui, Salma; Kaji, Mark D; Forrester, Sean G.

doi:10.1016/j.vetpar.2011.10.006

Cited by 27 publications

(31 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a result, treatment with piperazine leads to flaccid paralysis of parasites and the expulsion of the worms from the host (Abdi et al 1995). Brown et al (2012) showed that piperazine activates the Hco-UNC-49 receptor at high concentrations; in the mM range-consistent with the low potency of piperazine on Ascaris muscle tissue.…”

Section: Nematicidal Drugs Targeting Cys-loop Gaba Receptorssupporting

confidence: 64%

“…Conversely, the Cel-UNC-49B subunit possesses a conserved threonine at the 6 0 position, resulting in a PTX sensitive channel when it is assembled as a homomeric channel (Bamber et al 2003). The same methionine is present in the H. contortus UNC-49C subunit, which also causes heteromeric channels to become relatively insensitive to PTX Brown et al 2012). Furthermore, unlike mammalian GABA A receptors, the UNC-49 receptor is relatively insensitive to bicuculline inhibition or benzodiazepine enhancement and, unlike the Drosophilia RDL receptors, is insensitive to dieldrin (Bamber et al 2003;Brown et al 2012).…”

Section: The Unc-49 Gaba Receptormentioning

confidence: 99%

“…The same methionine is present in the H. contortus UNC-49C subunit, which also causes heteromeric channels to become relatively insensitive to PTX Brown et al 2012). Furthermore, unlike mammalian GABA A receptors, the UNC-49 receptor is relatively insensitive to bicuculline inhibition or benzodiazepine enhancement and, unlike the Drosophilia RDL receptors, is insensitive to dieldrin (Bamber et al 2003;Brown et al 2012). Overall, the unique pharmacology of the UNC-49 receptor mostly resembles that of the GABA receptor characterized in Ascaris muscle (Holden-Dye et al 1989;Walker et al 1992;Martin 1993).…”

Section: The Unc-49 Gaba Receptormentioning

confidence: 99%

See 2 more Smart Citations

Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics

2012

Self Cite

View full text Add to dashboard Cite

Parasitic nematode infection of humans and livestock is a major problem globally. Attempts to control nematode populations have led to the development of several classes of anthelmintic, which target cys-loop ligand-gated ion channels. Unlike the vertebrate nervous system, the nematode nervous system possesses a large and diversified array of ligand-gated chloride channels that comprise key components of the inhibitory neurotransmission system. In particular, cys-loop GABA receptors have evolved to play many fundamental roles in nematode behaviour such as locomotion. Analysis of the genomes of several free-living and parasitic nematodes suggests that there are several groups of cys-loop GABA receptor subunits that, for the most part, are conserved among nematodes. Despite many similarities with vertebrate cys-loop GABA receptors, those in nematodes are quite distinct in sequence similarity, subunit composition and biological function. With rising anthelmintic resistance in many nematode populations worldwide, GABA receptors should become an area of increased scientific investigation in the development of the next generation of anthelmintics.

show abstract

Section: Nematicidal Drugs Targeting Cys-loop Gaba Receptorssupporting

confidence: 64%

Section: The Unc-49 Gaba Receptormentioning

confidence: 99%

Section: The Unc-49 Gaba Receptormentioning

confidence: 99%

See 1 more Smart Citation

Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics

2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…The primary target of IVM is the invertebrate glutamate-gated chloride channel (GluCl) (Cully et al, 1994(Cully et al, , 1996Janssen et al, 2007Janssen et al, , 2010McCavera et al, 2009;Moreno et al, 2010), though it also has efficacy against other members of the invertebrate Cys-loop family of neurotransmitter receptors including the γ-aminobutyric acid- (Brown et al, 2012), histamine- (Zheng et al, 2002) and pHsensitive chloride channels (Schnizler et al, 2005). Because IVM is used to control and treat parasitic nematode diseases (Õmura, 2008), the majority of research on IVM targets has occurred in nematodes or model organisms, but the function of GluCl in mosquito disease vectors is unknown.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

Meyers

Gray

Kuklinski

et al. 2015

Journal of Experimental Biology

View full text Add to dashboard Cite

The use of insecticide-treated nets and indoor residual insecticides targeting adult mosquito vectors is a key element in malaria control programs. However, mosquito resistance to the insecticides used in these applications threatens malaria control efforts. Recently, the mass drug administration of ivermectin (IVM) has been shown to kill Anopheles gambiae mosquitoes and disrupt Plasmodium falciparum transmission in the field. We cloned the molecular target of IVM from A. gambiae, the glutamate-gated chloride channel (AgGluCl), and characterized its transcriptional patterns, protein expression and functional responses to glutamate and IVM. AgGluCl cloning revealed an unpredicted fourth splice isoform as well as a novel exon and splice site. The predicted gene products contained heterogeneity in the N-terminal extracellular domain and the intracellular loop region. Responses to glutamate and IVM were measured using two-electrode voltage clamp on Xenopus laevis oocytes expressing AgGluCl. IVM induced non-persistent currents in AgGluCl-a1 and did not potentiate glutamate responses. In contrast, AgGluCl-b was insensitive to IVM, suggesting that the AgGluCl gene could produce IVM-sensitive and -insensitive homomultimers from alternative splicing. AgGluCl isoformspecific transcripts were measured across tissues, ages, blood feeding status and sex, and were found to be differentially transcribed across these physiological variables. Lastly, we stained adult, female A. gambiae for GluCl expression. The channel was expressed in the antenna, Johnston's organ, supraesophageal ganglion and thoracic ganglia. In summary, we have characterized the first GluCl from a mosquito, A. gambiae, and described its unique activity and expression with respect to it as the target of the insecticide IVM.

show abstract

“…[35][36][37] In addition, ivermectin exposure alters expression of genes involved in the reproduction mechanism of female worms, even at low concentrations. 38,39 Latterly, research has indicated that glutamate-gated chloride channels activity is solely expressed in musculature surrounding the filarial excretory-secretory vesicle, suggesting that chemicals originating from the excretory-secretory vesicle are regulated by the activity.…”

Section: The Present: a Puzzlementioning

confidence: 99%

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

2017

View full text Add to dashboard Cite

Over the past decade, the global scientific community have begun to recognize the unmatched value of an extraordinary drug, ivermectin, that originates from a single microbe unearthed from soil in Japan. Work on ivermectin has seen its discoverer, Satoshi Ōmura, of Tokyo's prestigious Kitasato Institute, receive the 2014 Gairdner Global Health Award and the 2015 Nobel Prize in Physiology or Medicine, which he shared with a collaborating partner in the discovery and development of the drug, William Campbell of Merck & Co. Incorporated. Today, ivermectin is continuing to surprise and excite scientists, offering more and more promise to help improve global public health by treating a diverse range of diseases, with its unexpected potential as an antibacterial, antiviral and anti-cancer agent being particularly extraordinary.

show abstract

Pharmacological characterization of the Haemonchus contortus GABA-gated chloride channel, Hco-UNC-49: Modulation by macrocyclic lactone anthelmintics and a receptor for piperazine

Cited by 27 publications

References 24 publications

Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics

Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

Contact Info

Product

Resources

About