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Biomedical subjects

M Connor

Publications and source records attributed to M Connor.

At least 37 records · Page 2Linked to original sources

The Roper, Logan and Tierney (1996) model: perceptions and operationalization of the model in psychiatric nursing within a health board in Ireland.

This study aimed to determine whether the Roper, Logan & Tierney model was an appropriate model for planning nursing care for clients who are mentally ill. Data were collected from two sources in one Health Board region in Ireland. A care plan audit was used to evaluate the extent to which the Roper, Logan & Tierney model was used to assess, plan and evaluate nursing care in nursing documentation. Qualitative interviews with nurses explored their experiences of using the model and their perceptions of the model's usefulness and appropriateness for planning care. Both data sets were complementary, the qualitative data often providing contextual information which helped put the findings into perspective. It was found that there was little evidence that the Roper, Logan and Tierney model guided care planning and that goals and nursing interventions were frequently not explicitly documented. Interviews with nurses indicated that they lacked educational preparation for using the model and found the model constraining and physically orientated. The appropriateness of the Roper, Logan and Tierney model for planning care for clients who are mentally ill is questioned. It is suggested that nurses need to be adequately prepared if they are to use a model appropriately. Consideration should be given when selecting a model as to its 'fit' with the needs of the client group and the ward team philosophy.

Attitude of Health Personnel↗

Cellular actions of opioids and other analgesics: implications for synergism in pain relief.

1. mu-Opioid receptor agonists mediate their central analgesic effects by actions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, mu-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We have established that mu-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid. 2. At a cellular level, mu-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage-gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG. 3. The mu-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A2 inhibitors and non-specific LOX and specific 12-LOX inhibitors. Cyclo-oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of mu-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of mu-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors.

Analgesics↗

Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro.

The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-mediated analgesia in the central nervous system. In the present study, we examined the actions of cannabinoids on rat PAG neurons in vitro. In brain slices, superfusion of the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked inhibitory and excitatory postsynaptic currents in all PAG neurons. The endogenous cannabinoid anandamide inhibited evoked inhibitory postsynaptic currents in the presence of the anandamide transport inhibitor AM404, but not in its absence. The stable anandamide analog R1-methanandamide also inhibited evoked inhibitory postsynaptic currents. WIN55,212-2 reduced the rate of spontaneous miniature inhibitory postsynaptic currents in normal and Ca(2+)-free solutions, but had no effect on their amplitude distributions or kinetics. The WIN55,212-2-induced decrease in miniature inhibitory postsynaptic current rate was concentration dependent (EC(50) = 520 nM). The effects of cannabinoids were reversed by the CB(1) receptor antagonist SR141716. WIN55,212-2 produced no change in membrane current or conductance in PAG neurons in brain slices and had no effect on Ca(2+)-channel currents in acutely isolated PAG neurons. These findings suggest that cannabinoids act via CB(1) receptors to inhibit GABAergic and glutamatergic synaptic transmission in rat PAG, although the efficacy of endogenous cannabinoids is likely to be limited by uptake and breakdown. Like mu-opioids, cannabinoids act to reduce the probability of transmitter release from presynaptic terminals via a Ca(2+)-independent mechanism. In contrast to mu-opioids, cannabinoids have no direct postsynaptic actions on PAG neurons. Thus, cannabinoids and mu-opioids are likely to produce analgesia within PAG in part by different mechanisms.

Animals↗

Mu-opioid receptor modulation of calcium channel current in periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1.

1. The actions of opioid receptor agonists on the calcium channel currents (IBa) of acutely dissociated periaqueductal grey (PAG) neurons from C57B16/J mice and mutant mice lacking the first exon of the mu-opioid receptor (MOR-1) were examined using whole cell patch clamp techniques. These effects were compared with the GABA(B)-receptor agonist baclofen. 2. The endogenous opioid agonist methionine-enkephalin (met-enkephalin, pEC50 6.8, maximum inhibition 40%), the putative endogenous mu-opioid agonist endomorphin-1 (pEC50 6.2, maximum inhibition 35%) and the mu-opioid selective agonist DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin, pEC50 6.9, maximum inhibition 40%) inhibited IBa in 70% of mouse PAG neurons. The inhibition of IBa by each agonist was completely prevented by the mu-receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2). The delta-opioid receptor agonists DPDPE ([D-Pen2,5]enkephalin, 1 microM) and deltorphin II (1 microM), and the kappa-opioid receptor agonist U-69593 (1-10 microM), did not affect IBa in any cell tested. 3. The GABA(B) agonist baclofen inhibited IBa in all neurons (pEC50 5.9, maximum inhibition 42%). 4. In neurons from the MOR-1 deficient mice, the mu-opioid agonists met-enkephalin, DAMGO and endomorphin-1 did not inhibit IBa, whilst baclofen inhibited IBa in a manner indistinguishable from wild type mice. 5. A maximally effective concentration of endomorphin-1 (30 microM) partially (19%), but significantly (P<0.005), occluded the inhibition of IBa normally elicited by a maximally effective concentration of met-enkephalin (10 microM). 6. This study indicates that mu-opioid receptors, but not delta- or kappa-opioid receptors, modulate somatic calcium channel currents in mouse PAG neurons. The putative endogenous mu-agonist, endomorphin-1, was a partial agonist in mouse PAG neurons.

Animals↗

Continued morphine modulation of calcium channel currents in acutely isolated locus coeruleus neurons from morphine-dependent rats.

1. The actions of the opioid agonists morphine and methionine-enkephalin (met-enkephalin) on the calcium channel currents (IBa) of acutely isolated locus coeruleus (LC) neurons from morphine-dependent and vehicle-treated rats were examined using whole cell patch clamp techniques. 2. In LC neurons maintained in 5 microM morphine, co-superfusion of naloxone (1 microM) or the mu-opioid receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 1 microM) with morphine resulted in a significant increase in the amplitude of IBa. The increases in IBa were not different in neurons from morphine-dependent or vehicle rats. The increase in IBa was mimicked by washing off morphine, but not by co-superfusion of the kappa-receptor antagonist norbinaltorphimine (300 nM) or the delta-receptor antagonist ICI-174864 (1 microM). 3. In spontaneously withdrawn LC neurons from morphine-dependent rats, met-enkephalin (pD2 7.1, maximum inhibition 49%) and morphine (pD2 6.5, maximum inhibition 33%), inhibited IBa in all cells. In cells from vehicle rats the pD2 for met-enkephalin was 7.3, maximum inhibition 52%, while the pD2 for morphine was 6.6 and the maximum inhibition 43% (P<0.05 versus cells from morphine-dependent rats). 4. IBa in LC neurons was mostly comprised of omega-conotoxin GVIA- (N-type) and omega-agatoxin IVA- (P/Q-type) sensitive components, with lesser amounts of nimodipine-sensitive current and current resistant to all three blockers. Neither the density of IBa nor the proportion of any of the components of IBa differed between neurons from morphine-dependent or vehicle-treated rats. 5. This study demonstrates that in morphine-dependent rats, morphine and met-enkephalin modulation of somatic IBa in LC neurons displays modest tolerance compared with untreated rats. Further, chronic morphine treatment does not alter the type or density of IBa in LC neurons. These results provide more evidence that functional mu-opioid receptor coupling is not dramatically altered in the LC in morphine-dependent rats.

Analgesics, Opioid↗

Nociceptin, Phe(1)psi-nociceptin(1 - 13), nocistatin and prepronociceptin(154 - 181) effects on calcium channel currents and a potassium current in rat locus coeruleus in vitro.

1. The actions of the neuropeptide nociceptin, the putative nociceptin receptor antagonist [Phe1psi(CH(2)-NH)Gly(2)]-nociceptin-(1 - 13)NH(2) (Phe(1)psi-nociceptin(1 - 13)) and the putative nociceptin precursor products nocistatin (rat prepronociceptin(125 - 132)) and rat prepronociceptin(154 - 181) were examined on membrane properties of rat locus coeruleus (LC) neurons using whole cell patch clamp techniques. 2. Nociceptin inhibited I(Ba) in all LC neurons, (pD(2) of 8.9, maximum inhibition 50%). The inhibition of I(Ba) by nociceptin was associated with slowing of the activation of I(Ba) and could be significantly reversed by a strong depolarizing prepulse. Phe(1)psi-nociceptin(1 - 13) also inhibited I(Ba) in LC neurons (notional pD(2) of 7.6, maximum inhibition 18%). Application of Phe(1)psi-nociceptin(1 - 13) (1 microM) significantly occluded the subsequent effects of a co-application of nociceptin (3 nM) on I(Ba). 3. As previously reported for nociceptin, Phe(1)psi-nociceptin(1 - 13) caused an outward current in LC neurons voltage clamped at -60 mV (pD(2) of 7.1, maximum current 50% of that of methionine enkephalin, 10 microM). The Phe(1)psi-nociceptin(1 - 13) induced current reversed polarity at -112 mV and exhibited pronounced inward rectification. Phe(1)psi-nociceptin(1 - 13) (1 microM) reversibly inhibited the current caused by nociceptin (300 nM) by 30%. 4. Neither nocistatin nor rat prepronociceptin(154 - 181) inhibited I(Ba) in LC neurons, or prevented the subsequent inhibition by nociceptin. Neither nocistatin or prepronociceptin(154 - 181) affected the membrane properties of LC neurons. 5. This study demonstrates that nociceptin modulates somatic I(Ba) in rat LC neurons. The putative ORL1 antagonist Phe(1)psi-nociceptin(1 - 13) exhibited partial agonist activity at inhibiting I(Ba) and opening K(+) channels in LC. Other putative nociceptin precursor products were without effect on LC cells.

Animals↗

The effect of age on vascular compliance in man: which are the appropriate measures?

Vascular compliance declines rapidly with age and measures of arterial compliance may help understanding of the aging process. Of the different measures of vascular compliance, those more closely related to chronological age need to be identified. These measures may help in the estimation of 'biological age'. We measured pulse wave velocity as the carotid-finger interval, carotid-toe interval and QKD interval (time between the Q wave and the arrival of the diastolic Korotkoff sound (K) over the brachial artery in diastoly (D)); central aortic compliance (CAC) and SV/PP (the stroke volume divided by pulse pressure in the brachial artery). Thirty-six volunteers were studied (30 men), ages 20 to 84, mean 49 years, to give the relationship of these measurements with age. CAC, the QKD interval and the carotid-toe interval were most closely related to age (r = - 0.51, -0.60 and -0.58 respectively). After adjustment for age, the only measure related to blood pressure was the carotid-finger interval; b for diastolic blood pressure = -0.83 (P = 0.01), the higher the pressure the shorter the interval. Measurements of CAC, QKD interval and carotid-toe interval may be employed to assess the impact of age on vascular compliance. Measures of peripheral vascular compliance, such as the carotid-finger interval, may prove useful in assessing the relationship between blood pressure and vascular compliance.

Adult↗

High-resolution solution structure of gurmarin, a sweet-taste-suppressing plant polypeptide.

Gurmarin is a 35-residue polypeptide from the Asclepiad vine Gymnema sylvestre. It has been utilised as a pharmacological tool in the study of sweet-taste transduction because of its ability to selectively inhibit the neural response to sweet tastants in rats. We have chemically synthesised and folded gurmarin and determined its three-dimensional solution structure to high resolution using two-dimensional NMR spectroscopy. Structure calculations utilised 612 interproton-distance, 19 dihedral-angle, and 18 hydrogen-bond restraints. The structure is well defined for residues 3-34, with backbone and heavy atom rms differences of 0.27 +/- 0.09 A and 0.73 +/- 0.09 A, respectively. Gurmarin adopts a compact structure containing an antiparallel beta-hairpin (residues 22-34), several well-defined beta-turns, and a cystine-knot motif commonly observed in toxic and inhibitory polypeptides. Despite striking structural homology with delta-atracotoxin, a spider neurotoxin known to slow the inactivation of voltage-gated Na+ channels, we show that gurmarin has no effect on a variety of voltage-sensitive channels.

Amino Acid Sequence↗

Opioid receptor signalling mechanisms.

1. Three pharmacological types of opioid receptors, mu, delta and kappa, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from mu, delta and kappa receptors. 2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G-proteins. The mu, delta and kappa receptors are all capable of interacting with the pertussis toxin-sensitive G-protein alpha-subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin-insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and mu receptors do not activate Gq, G11, G12, G13, or G14. 3. Differential coupling of different opioid receptors to most types of G-proteins is marginal. The mu, delta and kappa receptors appear to preferentially activate Go and Gi2 over other pertussis toxin-sensitive G-proteins, although there is evidence that mu receptors show some preference for Gi3. delta Receptors couple more efficiently to G16 than do mu or kappa receptors. 4. There is some evidence that opioid receptors, particularly mu and ORL1 receptors, can also couple to cellular effectors in a G-protein-independent manner. 5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G-proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.

Animals↗

Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway.

Chronic morphine administration induces adaptations in neurons resulting in opioid tolerance and dependence. Functional studies have implicated a role for the periaqueductal gray area (PAG) in the expression of many signs of opioid withdrawal, but the cellular mechanisms are not fully understood. This study describes an increased efficacy, rather than tolerance, of opioid agonists at mu-receptors on GABAergic (but not glutamatergic) nerve terminals in PAG after chronic morphine treatment. Opioid withdrawal enhanced the amplitudes of electrically evoked inhibitory synaptic currents mediated by GABAA receptors and increased the frequency of spontaneous miniature GABAergic synaptic currents. These effects were not blocked by 4-aminopyridine or dendrotoxin, although both Kv channel blockers abolish acute opioid presynaptic inhibition of GABA release in PAG. Instead, the withdrawal-induced increases were blocked by protein kinase A inhibitors and occluded by metabolically stable cAMP analogs, which do not prevent acute opioid actions. These findings indicate that opioid dependence induces efficacious coupling of mu-receptors to presynaptic inhibition in GABAergic nerve terminals via adenylyl cyclase- and protein kinase A-dependent processes in PAG. The potential role of these adaptations in expression of withdrawal behavior was supported by inhibition of enhanced GABAergic synaptic transmission by the alpha2 adrenoceptor agonist clonidine. These findings provide a cellular mechanism that is consistent with other studies demonstrating attenuated opioid withdrawal behavior after injections of protein kinase A inhibitors into PAG and suggest a general mechanism whereby opioid withdrawal may enhance synaptic neurotransmission.

4-Aminopyridine↗

delta-Atracotoxins from australian funnel-web spiders compete with scorpion alpha-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels.

delta-Atracotoxins from the venom of Australian funnel-web spiders are a unique group of peptide toxins that slow sodium current inactivation in a manner similar to scorpion alpha-toxins. To analyze their interaction with known sodium channel neurotoxin receptor sites, we studied their effect on [3H]batrachotoxin and 125I-Lqh II (where Lqh is alpha-toxin II from the venom of the scorpion Leiurus quinquestriatus hebraeus) binding and on alkaloid toxin-stimulated 22Na+ uptake in rat brain synaptosomes. delta-Atracotoxins significantly increased [3H]batrachotoxin binding yet decreased maximal batrachotoxin-activated 22Na+ uptake by 70-80%, the latter in marked contrast to the effect of scorpion alpha-toxins. Unlike the inhibition of batrachotoxin-activated 22Na+ uptake, delta-atracotoxins increased veratridine-stimulated 22Na+ uptake by converting veratridine from a partial to a full agonist, analogous to scorpion alpha-toxins. Hence, delta-atracotoxins are able to differentiate between the open state of the sodium channel stabilized by batrachotoxin and veratridine and suggest a distinct sub-conductance state stabilized by delta-atracotoxins. Despite these actions, low concentrations of delta-atracotoxins completely inhibited the binding of the scorpion alpha-toxin, 125I-Lqh II, indicating that they bind to similar, or partially overlapping, receptor sites. The apparent uncoupling between the increase in binding but inhibition of the effect of batrachotoxin induced by delta-atracotoxins suggests that the binding and action of certain alkaloid toxins may represent at least two distinguishable steps. These results further contribute to the understanding of the complex dynamic interactions between neurotoxin receptor site areas related to sodium channel gating.

Animals↗

Modulation of Ca2+ channel currents of acutely dissociated rat periaqueductal grey neurons.

1. The actions of the neuropeptide nociceptin on the calcium channel currents (IBa) of acutely dissociated rat periaqueductal grey (PAG) neurons were examined using whole-cell patch clamp techniques. These effects were compared with those of opioid receptor agonists and the GABAB receptor agonist baclofen. 2. Neurons from young adult rats (23 to 56 days old) expressed predominantly omega-conotoxin GVIA (N-type)- and omega-agatoxin IVA (P/Q-type)-sensitive IBa, together with smaller amounts of nimodipine-sensitive current and current resistant to all three blockers. There was proportionately more N-type IBa in neurons from female rats and proportionately more resistant current in neurons from male rats. 3. Nociceptin (EC50, 5 nM) and baclofen (EC50, 0.8 microM) inhibited IBa in all PAG neurons, while the opioid agonist methionine enkephalin (met-enkephalin; 300 nM-10 microM) inhibited IBa in 40 % of neurons. The effects of met-enkephalin were reversed by the mu-opioid antagonist CTAP, and mimicked by the mu-opioid agonist DAMGO (300 nM-3 microM). The delta-opioid agonists DPDPE and deltorphin II, and the kappa-opioid agonist U69593, did not affect IBa in any neuron. The actions of nociceptin were not mimicked or blocked by the opioid antagonist naloxone or the nociceptin analogue [desPhe1]-nociceptin. 4. The effects of nociceptin and baclofen on IBa were blocked by pretreatment of the neurons with pertussis toxin (500 ng ml-1, 8 h). 5. Nociceptin predominantly inhibited the N-type (EC50, 2 nM; maximum inhibition, 50 %) and P/Q-type (EC50, 7 nM; maximum inhibition, 33 %) IBa while having little effect on the L-type and R-type IBa. 6. These results are consistent with the previously described actions of nociceptin, baclofen and micro-opioids in PAG slices, whereby they couple to increases in an inwardly rectifying K+ conductance. These agonists thus have the potential to modulate the function of PAG neurons via a number of different cellular effectors.

Amino Acid Sequence↗

Genetics of psoriasis: paternal inheritance and a locus on chromosome 6p.

The pathogenesis of psoriasis is not fully understood, but population and twin studies suggest a large heritable component to the etiology. Several large population studies have also suggested a parental sex effect. Since 1994, three main genetic loci (on chromosomes 17q, 4q, and 6p) have been reported in genome scans. With a view to elucidating the genetic basis of psoriasis, we have carried out linkage analysis in a large number of families with well-characterized psoriasis. From a cohort of 1250 probands with psoriasis, 395 individuals (301 affected, 94 unaffected) in 103 families were recruited. Each subject was carefully examined by an experienced dermatologist and stringent diagnostic criteria applied. Genotypes were generated at 11 polymorphic loci on chromosomes 17q, 4q, and 6p and the results were analyzed parametrically and nonparametrically. In the population from which the probands were drawn, there was evidence of a parental sex effect, more probands having an affected father than an affected mother. Genetic anticipation was also apparent and most marked if the disease was inherited from the father. The loci on chromosomes 17 and 4 were not replicated but there was strong evidence for linkage to chromosome 6p (maximum two point LOD score 4.63 at D6S291). The evidence for linkage in sibling pair analysis was greatest when the allele was of paternal origin and was most significant in those families without psoriatic arthritis. These studies confirm the presence of a susceptibility gene on chromosome 6p. The available evidence suggests that a different genetic susceptibility may underlie psoriasis and psoriatic arthritis.

Age of Onset↗

Simplified surveillance for nosocomial bloodstream infections.

OBJECTIVE: To compare a surveillance definition of noso comial bloodstream infections requiring only microbiology data to the Centers for Disease Control and Prevention's (CDC) current definition. SETTING: Six teaching hospitals. METHODS: We classified a representative sample of 73 positive blood cultures from six hospitals growing common skin contaminant isolates using a definition for bacteremia requiring only microbiology data and the CDC definition for primary bloodstream infection (National Nosocomial Infections Surveillance [NNIS] System review method). The classifications assigned during routine prospective surveillance also were noted, and the time required to classify isolates by the two methods was compared. RESULTS: Among 65 blood cultures growing common skin contaminant isolates obtained from adults, the agreement rate between the microbiology data method and the NNIS review method was 91%. Agreement was significantly poorer for the eight blood cultures growing common skin contaminant isolates obtained from pediatric patients. The microbiology data method requires approximately 20 minutes less time per isolate than does routine surveillance. CONCLUSIONS: A definition based on microbiology data alone yields the same result as the CDC's definition in the large majority of instances. It is more resource-efficient than the CDC's current definition.

Adult↗

Bradykinin inhibition of N- and L-type calcium channel currents in NG108-15 cells.

The bradykinin regulation of calcium channel currents in NG108-15 neuroblastoma x glioma hybrid cells was examined, in order to determine: (1) which type of bradykinin receptors mediates the inhibition of N-type calcium channels in these cells; and (2) whether bradykinin can modulate other types of calcium channels in these cells. Bradykinin inhibited both N- and L-type calcium channels in NG108-15 cells, with EC50S of 10 +/- 2 nM and 29 +/- 7 nM, respectively. The inhibition of both L- and N-type calcium channels by bradykinin (100 nM) could be completely inhibited by the bradykinin B2 receptor antagonist Hoe 140 (10 nM). Bradykinin appeared to inhibit that portion of the L-type calcium channel current that was also reversibly inhibited by omega-conotoxin GVIA. The bradykinin inhibition of the L-type calcium channel current was partly reduced by pretreatment of the cells with pertussis toxin, whereas the inhibition of the N-type current was pertussis toxin-insensitive. In some cultures it was observed that the bradykinin B1 receptor agonist desArg9bradykinin inhibited the L-type calcium channel current.

Bradykinin↗

The structure of a novel insecticidal neurotoxin, omega-atracotoxin-HV1, from the venom of an Australian funnel web spider.

A family of potent insecticidal toxins has recently been isolated from the venom of Australian funnel web spiders. Among these is the 37-residue peptide omega-atracotoxin-HV1 (omega-ACTX-HV1) from Hadronyche versuta. We have chemically synthesized and folded omega-ACTX-HV1, shown that it is neurotoxic, ascertained its disulphide bonding pattern, and determined its three-dimensional solution structure using NMR spectroscopy. The structure consists of a solvent-accessible beta-hairpin protruding from a disulphide-bonded globular core comprising four beta-turns. The three intramolecular disulphide bonds from a cystine knot motif similar to that seen in several other neurotoxic peptides. Despite limited sequence identity, omega-ACTX-HV1 displays significant structural homology with the omega-agatoxins and omega-conotoxins, both of which are vertebrate calcium channel antagonists; however, in contrast with these toxins, we show that omega-ACTX-HV1 inhibits insect, but not mammalian, voltage-gated calcium channel currents.

Amino Acid Sequence↗