Characterization and comparative pharmacological studies of a functional γ-aminobutyric acid (GABA) receptor cloned from the tobacco budworm,Heliothis virescens (Noctuidae:Lepidoptera)

Wolff, Mark A.; Wingate, Vincent P. M.

doi:10.1007/bf02577690

Cited by 36 publications

(27 citation statements)

References 35 publications

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“…Similar levels of inhibition by 10 Ϫ5 moll Ϫ1 dieldrin in response to GABA-evoked currents after expression in Xenopus oocyte of the Drosophila and Heliothis RDL subunit were also reported by Wolff and Wingate (1998). Over the last 10 years three genes encoding subunits for GABA-mediated increases in Cl Ϫ conductance in Drosophila have been identified and cloned.…”

Section: Discussionsupporting

confidence: 63%

Differential sensitivity of two insect GABA-gated chloride channels to dieldrin, fipronil and picrotoxinin

Corronc

Alix

Hue

2002

Journal of Insect Physiology

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In the central nervous system of both vertebrates and invertebrates inhibitory neurotransmission is mainly achieved through activation of γ-aminobutyric acid (GABA) receptors. Extensive studies have established the structural and pharmacological properties of vertebrate GABA receptors. Although the vast majority of insect GABA-sensitive responses share some properties with vertebrate GABAA receptors, peculiar pharmacological properties of these receptors led us to think that several GABA-gated chloride channels are present in insects. We describe here the pharmacological properties of two GABA receptor subtypes coupled to a chloride channel on dorsal unpaired median (DUM) neurones of the adult male cockroach. Long applications of GABA induce a large biphasic hyperpolarization, consisting of an initial transient hyperpolarization followed by a slow phase of hyperpolarization that is not quickly desensitized. With GABA, the transient hyperpolarization is sensitive to picrotoxinin, fipronil and dieldrin whereas the slow response is insensitive to these insecticides.When GABA is replaced by muscimol and cis-4-aminocrotonic acid (CACA) a biphasic hyperpolarization consisting of an initial transient hyperpolarization followed by a sustained phase is evoked which is blocked by picrotoxinin and fipronil. Exposure to dieldrin decreases only the early phase of the muscimol and CACA-induced biphasic response, suggesting that two GABA-gated chloride channel receptor subtypes are present in DUM neurones. This study describes, for the first time, a dieldrin resistant component different to the dieldrin-and picrotoxinin-resistant receptor found in several insect species. 

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Section: Discussionsupporting

confidence: 63%

Differential sensitivity of two insect GABA-gated chloride channels to dieldrin, fipronil and picrotoxinin

Corronc

Alix

Hue

2002

Journal of Insect Physiology

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“…For example, bicuculline blocks ionotropic GABARs of some adult (Waldrop et al, 1987) and larval Manduca sexta abdominal ganglion neurons (Sattelle et al, 2003) as well as electrically evoked or odor-evoked inhibitory postsynaptic potentials and GABA responses in projection neurons of antennal lobes of this species (Christensen et al, 1998a,b). It is clear, however, that RDL and its equivalent cloned from Heliothis virescens (Wolff and Wingate, 1998) resemble, in their insensitivity to bicuculline, the majority of insect ionotropic GABARs.…”

Section: Rdl As a Model Of Native Insect Gaba Receptorsmentioning

confidence: 99%

“…Although RDL mimics well the agonist, competitive antagonist, and convulsant sites of insect GABARs, differences have emerged among RDL and known native insect GABARs in their sensitivity to benzodiazepines. For example, whereas the agonist responses of certain bicuculline-insensitive insect GABARs are enhanced by micromolar concentrations of flunitrazepam (Sattelle et al, 1988), the GABA responses of RDL homomers (Millar et al, 1994) or its H. virescens equivalent (Wolff and Wingate, 1998) are unaffected by flunitrazepam (100 M). More importantly, insect native GABARs and RDL homomers are both enhanced by lower concentrations of 4Ј-chlorodiazepam (Ro5-4864) (it inhibits native receptors at higher concentrations; R. Higashino and D. B. Sattelle, unpublished obervations), although RDL receptors were approximately 100-fold less sensitive to this compound than native insect receptors (Sattelle et al, 1988;Buckingham et al, 1996;Hosie and Sattelle, 1996b).…”

Section: Rdl As a Model Of Native Insect Gaba Receptorsmentioning

confidence: 99%

Insect GABA Receptors: Splicing, Editing, and Targeting by Antiparasitics and Insecticides

Buckingham¹,

Biggin²,

Sattelle³

et al. 2005

Mol Pharmacol

205

211

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Ionotropic GABA receptors are abundant in both vertebrate and invertebrate nervous systems, where they mediate rapid, mostly inhibitory synaptic transmission. A GABA-gated chloride channel subunit from Drosophila melanogaster [Resistant to Dieldrin (RDL)] has been cloned, functionally expressed, and found to exhibit many aspects of the pharmacology of native, bicuculline-insensitive insect GABA receptors. RDL is the target of the commercially important insecticide fipronil. A point mutation in the channel-lining region of the RDL molecule is known to underlie most cases of resistance to insecticides acting on GABA receptors. RDL is widely distributed throughout the insect nervous system, but the subunit composition of RDLcontaining in native receptors is unknown. It is possible that in some instances, RDL coexpresses with glutamate-gated chloride channel subunits. Other ionotropic receptor subunits (LCCH3 and GRD) form GABA-gated cation channels when heterologously expressed. Interest in RDL as a model ligandgated anion channel has been enhanced by the recent discovery of pre-mRNA A-to-I editing, which, together with alternative splicing, adds to the functional diversity of this GABA receptor subunit.Ionotropic GABA receptor molecules (GABARs) are members of the dicysteine-loop ('Cys-loop') superfamily of neurotransmitter receptors, which also includes nicotinic acetylcholine receptors, type 3 5-hydroxytryptamine receptors, and glycine receptors (Karlin and Akabas, 1995;Karlin, 2002;Olsen et al., 2004). Ionotropic GABARs are pentameric proteins. Each polypeptide subunit possesses a long N-terminal extracellular domain containing residues that contribute to the neurotransmitter binding site and four transmembrane regions (M1-M4), the second of which (M2) provides many of the residues that line the integral chloride channel (Whiting, 2003;Kim et al., 2004;Darlison et al., 2005). Vertebrate ionotropic GABARs may be divided into two pharmacological categories: bicuculline-sensitive GABA A receptors (composed of ␣ 1-6 , ␤ 1-3 , ␥ 1-3 , ␦, ⑀, , and 1-3 subunits and allosterically modulated by benzodiazepines and barbiturates as well as pregnane steroids) and bicuculline-insensitive GABA C receptors (composed of the three known isoforms of the subunit and insensitive to the majority of modulators of GABA A receptors) (Mustafa, 1995;Sieghart, 1995;McKernan and Whiting, 1996;Whiting, 2003;Connolly and Wafford, 2004;Rudolph and Mohler, 2004). This division into A and C subtypes is difficult to reconcile with recent findings on GABARs in brainstem neurons, which are composed of 1 subunits coexpressed with ␣1 and ␥2 subunits (Milligan et al., 2004) to yield receptors with properties of both GABA A and GABA C subtypes. Furthermore, GABA A and GABA B receptors, which differ structurally and in their signaling mechanisms, may be closely functionally coupled. This is supported by the recent finding that the GABA A ␥2S subunit forms a complex with GABA B R1 subunits (thereby enhancing GABA B receptor trafficking to the c...

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“…On the other hand, Rdl is also a component of GluCls in insects (Ludmerer et al, 2002), and although this may be unimportant in terms of dieldrin resistance, it could play a role in the development of resistance of fipronil, which also potently blocks GluCls. Heterologously expressed Rdl homomultimers containing the resistance mutation may display reduced sensitivity to fipronil in some cases (Wolff and Wingate, 1998) that, although much less than the resistance to dieldrin, could lead to moderate levels of resistance to fipronil in some species, which is in fact seen (Cole et al, 1995). Studies of the action of fipronil against native GABA and nondesensitizing GluCls in insects with the Rdl resistance mechanism are needed to fully understand the moderate resistance to fipronil.…”

Section: Fipronil On Glutamate Chloride Channels 199mentioning

confidence: 99%

“…Furthermore, after several years of use in more than 60 countries, the field performance of fipronil has not been hampered by resistance. The Ala-Ser mutation of the Drosophila (DMRd1) GABA receptor is not associated with reduced fipronil sensitivity (Hosie et al, 1995), but equivalent mutation of Heliothis GABA receptor (HVDRL) showed reduced sensitivity to fipronil (Wolff and Wingate, 1998). Thus, a target site other than Rdl GABA receptor might be involved in the effectiveness of fipronil on dieldrin-resistant insects.…”

mentioning

confidence: 98%

Fipronil Is a Potent Open Channel Blocker of Glutamate-Activated Chloride Channels in Cockroach Neurons

Zhao

Yeh²,

Salgado

et al. 2004

J Pharmacol Exp Ther

136

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Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC 50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that fipronil blocks required channel opening. Recovery of the desensitizing current from fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to fipronil block. It is concluded that GluCls are a critical target for fipronil, especially for the selective toxicity between mammals and insects, and that fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.

show abstract

Characterization and comparative pharmacological studies of a functional γ-aminobutyric acid (GABA) receptor cloned from the tobacco budworm,Heliothis virescens (Noctuidae:Lepidoptera)

Cited by 36 publications

References 35 publications

Differential sensitivity of two insect GABA-gated chloride channels to dieldrin, fipronil and picrotoxinin

Differential sensitivity of two insect GABA-gated chloride channels to dieldrin, fipronil and picrotoxinin

Insect GABA Receptors: Splicing, Editing, and Targeting by Antiparasitics and Insecticides

Fipronil Is a Potent Open Channel Blocker of Glutamate-Activated Chloride Channels in Cockroach Neurons

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