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PubMed2001

Solution structure and backbone dynamics of an omega-conotoxin precursor.

Nuclear magnetic resonance spectroscopy was used to characterize the solution structure and backbone dynamics of a putative precursor form of omega-conotoxin MVIIA, a 25-amino-acid residue peptide antagonist of voltage-gated Ca(2+) channels. The mature peptide is found in the venom of a fish-hunting marine snail Conus magus and contains an amidated carboxyl terminus that is generated by oxidative cleavage of a Gly residue. The form examined in this study is identical to the mature peptide except for the presence of the unmodified carboxy-terminal Gly. This form, referred to as omega-MVIIA-Gly, has previously been shown to refold and form its disulfides more efficiently than the mature form, suggesting that the presence of the terminal Gly may favor folding in vivo. The nuclear magnetic resonance (NMR) structure determination indicated that the fold of omega-MVIIA-Gly is very similar to that previously determined for the mature form, but revealed that the terminal Gly residue participates in a network of hydrogen bonds involving both backbone and side chain atoms, very likely accounting for the enhanced stability and folding efficiency. (15)N relaxation experiments indicated that the backbone is well ordered on the nanosecond time scale but that residues 9-15 undergo a conformational exchange processes with a time constant of approximately 35 microseconds. Other studies have implicated this segment in the binding of the peptide to its physiological target, and the observed motions may play a role in allowing the peptide to enter the binding site

Calcium Channel Blockers↗

PubMed2006

Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors.

Alpha-conotoxins from Conus snails are indispensable tools for distinguishing various subtypes of nicotinic acetylcholine receptors (nAChRs), and synthesis of alpha-conotoxin analogs may yield novel antagonists of higher potency and selectivity. We incorporated additional positive charges into alpha-conotoxins and analyzed their binding to nAChRs. Introduction of Arg or Lys residues instead of Ser12 in alpha-conotoxins GI and SI, or D12K substitution in alpha-conotoxin SIA increased the affinity for both the high- and low-affinity sites in membrane-bound Torpedo californica nAChR. The effect was most pronounced for [D12K]SIA with 30- and 200-fold enhancement for the respective sites, resulting in the most potent alpha-conotoxin blocker of the Torpedo nAChR among those tested. Similarly, D14K substitution in alpha-conotoxin [A10L]PnIA, a blocker of neuronal alpha7 nAChR, was previously shown to increase the affinity for this receptor and endowed [A10L,D14K]PnIA with the capacity to distinguish between acetylcholine-binding proteins from the mollusks Lymnaea stagnalis and Aplysia californica. We found that [A10L,D14K]PnIA also distinguishes two alpha7-like anion-selective nAChR subtypes present on identified neurons of L. stagnalis: [D14K] mutation affected only slightly the potency of [A10L]PnIA to block nAChRs on neurons with low sensitivity to alpha-conotoxin ImI, but gave a 50-fold enhancement of blocking activity in cells with high sensitivity to ImI. Therefore, the introduction of an additional positive charge in the C-terminus of alpha-conotoxins targeting some muscle or neuronal nAChRs made them more discriminative towards the respective nAChR subtypes. In the case of muscle-type alpha-conotoxin [D12K]SIA, the contribution of the Lys12 positive charge to enhanced affinity towards Torpedo nAChR was rationalized with the aid of computer modeling.

Amino Acid Sequence↗

PubMed1989

Geographutoxin-sensitive and insensitive sodium currents in mouse skeletal muscle developing in situ.

1. The whole-cell voltage-clamp technique was used to examine developmental changes of Na+ current properties in single fibres of mouse flexor digitorum brevis muscles developing in situ from birth to 20 days post-natal. 2. Geographutoxin II (GTX II), a novel polypeptide toxin from the marine snail Conus geographus, distinguished two different types of voltage-sensitive Na+ currents: GTX II-sensitive and GTX II-insensitive currents, which corresponded respectively to currents with high or low TTX sensitivity. 3. Voltage-dependent activation and inactivation of the GTX II-insensitive currents occurred at membrane potentials 10-20 mV more negative than those for the GTX II-sensitive currents. 4. The GTX II-insensitive current in fibres from mice older than 8 days inactivated more slowly than the GTX II-sensitive current. However, in fibres from younger mice, the two currents decayed with similar speed. 5. The mean specific Na+ conductance (gNa) for the total (GTX II-sensitive plus GTX II-insensitive) Na+ channels was 0.22 mS/muF at a Na+ concentration of 5 mM at birth. The total gNa increased 6-fold to 1.32 mS/muF during the first 20 days after birth. 6. The mean specific gNa for the GTX II-insensitive channels was 0.15 mS/muF at birth, remained at approximately the same level for the first 8 days, and then decreased progressively to become undetectable by day 16. 7. In muscle fibres denervated 12 days after birth, the GTX II-insensitive gNa increased over the next 8 days, whereas the total gNa increased less than normal. 8. By contrast, in fibres denervated on day 4, the total gNa increased more than normal in the following 8 days, and the GTX II-insensitive specific gNa increased above the level seen at birth. 9. Half-maximal activation and inactivation potentials of the total and the GTX II-insensitive currents shifted in the negative direction by 9-17 mV in the first 8 days after birth. 10. We conclude that the regulatory effects of innervation on the total gNa are either suppressive or enhancing depending on the stage of development. On the other hand, denervation elicits an increase in GTX II-insensitive Na+ currents at all ages studied.

Aging↗

PubMed1989

Calcium channels in solitary retinal ganglion cells from post-natal rat.

1. Calcium currents from identified, post-natal retinal ganglion cell neurones from rat were studied with whole-cell and single-channel patch-clamp techniques. Na+ and K+ currents were suppressed with pharmacological agents, allowing isolation of current carried by either 10 mM-Ca2+ or Ba2- during whole-cell recordings. For cell-attached patch recordings, the recording pipette contained 96-110 mM-BaCl2 while the bath solution consisted of isotonic potassium aspartate in order to zero the neuronal membrane potential. 2. A transient component, present in approximately one-third of the whole-cell recordings resembles closely the T-type calcium current observed previously in other tissues. This component activates at low voltages (-40 to -50 mV from holding potentials negative to -80 mV), inactivates with a time constant of 10-30 ms at 35 degrees C, and is carried equally well by Ba2+ or Ca2+. In single-channel recordings small (8 pS) channels are observed whose aggregate microscopic kinetics correspond well to the macroscopic current obtained during whole-cell measurements. 3. During whole-cell recordings, a more prolonged component activates in all retinal ganglion cells at -40 to -20 mV from a holding potential of -90 mV. This component is substantially larger when equimolar Ba2+ replaces Ca2+ as the charge carrier, and is sensitive to the dihydropyridine agonist Bay K8644 (5 microM) and antagonists nifedipine (1-10 microM) and nimodipine (1-10 microM). Thus, the dihydropyridine pharmacology of this prolonged component resembles that of the L-type calcium current found in dorsal root ganglion neurones and in heart cells. Also reminiscent of the L-current, the prolonged component in this preparation is less inactivated at depolarized holding potentials (-60 to -40 mV) than the transient component. In cell-attached recordings, large (20 pS) channels are observed with activation properties similar to those of the prolonged portion of the whole-cell current. 4. omega-Conotoxin fraction GVIA (omega-CgTX VIA), a peptide from the venom of the snail Conus geographus, produces a readily reversible blockade of all components of the calcium current in these central mammalian neurones. This finding is in contrast to that of other preparations in which this toxin is responsible for an ephemeral block of T-current but a long-lasting block of other components of calcium current. 5. In summary, at least two components of calcium current with discrete underlying unitary events are present in post-natal retinal ganglion cells from rat. One component closely resembles the T or transient current observed in other cell types.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.

Conantokin G (Con G) is a 17-amino-acid peptide antagonist of N-methyl-D-aspartate (NMDA) receptors isolated from the venom of the marine cone snail, Conus geographus. The mechanism of action of Con G has not been well defined; both competitive and noncompetitive interactions with the NMDA-binding site have been proposed. In this study the mechanism of action and subunit selectivity of Con G was examined in whole-cell voltage-clamp recordings from cultured neurons and in two electrode voltage-clamp recordings from Xenopus oocytes expressing recombinant NMDA receptors. Con G was a potent and selective antagonist of NMDA-evoked currents in murine cortical neurons (IC(50) = 480 nM). The slow onset of Con G block could be prevented by coapplication with high concentrations of NMDA or of the competitive antagonist (RS)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid. Furthermore, in oocytes expressing NR1a/NR2B receptors, Con G produced a rightward shift in the concentration-response curve for NMDA, providing support for a competitive interaction with the NMDA-binding site. Con G produced an apparent noncompetitive shift in the concentration-response curve for spermine potentiation of NMDA responses, but this was due to spermine-induced enhancement of Con G block. Spermine produced a similar enhancement of DL-2-amino-S-phosphopentanoic acid block. Finally, Con G selectively blocked NMDA receptors containing the NR2B subunit. These results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors. The unique subunit selectivity profile of Con G may explain its favorable in vivo profile compared with nonselective NMDA antagonists.

Animals↗

PubMedDate not supplied

Ziconotide: can we use it in palliative care?

Ziconotide (PRIALT) is a new nonopioid treatment for chronic pain. It is a peptide that is the synthetic analog of the omega-conotoxin, derived from the marine snail, Conus magus. The therapeutic benefit of ziconotide derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels. Interference with these channels inhibits input from pain-sensing primary nociceptors. A recent clinical trial demonstrated that ziconotide has a significant analgesic effect compared to placebo in patients considered intolerant or refractory to other treatment such as systemic analgesics, adjunctive therapies, or intrathecal (IT) morphine. Thus, ziconotide is the first of a new class of agents--N-type calcium channel blockers, or NCCBs. Ziconotide may represent another option for patients with refractory pain.

Analgesics, Non-Narcotic↗

PubMed1988

Optical studies of the secretory event at vertebrate nerve terminals.

Potentiometric probes are small (300-500 Mr) amphipatic molecules that bind to, but do not cross, cell membranes and behave as fast linear transducers of membrane voltage. Their optical properties, particularly absorbance and fluorescence, respond to changes in potential in less than 2 microseconds, and they may be used to follow electrical events in membranes which are inaccessible to microelectrodes. We have used these dyes to study the properties of the action potential in the neurosecretory terminals of vertebrate neurohypophyses and, in particular, to investigate the behaviour of the local population of calcium channels. These channels are sensitive to the peptide toxin omega-conotoxin GVIA, derived from the venom of the marine snail Conus geographicus, but insensitive to dihydropyridine channel modulators. In the neurohypophysis of the mouse, it is possible to demonstrate that the calcium channels that are blocked by omega-conotoxin are those that are required for secretion of peptide hormones. In the terminals of the neurohypophysis, excitation is coupled to secretion, and the secretory event is accompanied by large and rapid changes in light scattering. These intrinsic optical signals provide a millisecond time-resolved monitor of events in the terminal that follow the entry of calcium, and may precede the release of hormones. We will consider how the changes in light scattering can be related to secretion, and how the extrinsic (absorption) and intrinsic optical signals may provide complementary information about excitation-secretion coupling.

Action Potentials↗

PubMed2006

Ziconotide: a new option for refractory pain.

Ziconotide has been introduced as a new nonopioid treatment for chronic pain. Structurally, it is a peptide, the synthetic analog of the omega-conotoxin, derived from the marine snail, Conus magus. N-type voltage-sensitive calcium channels play a role in the transmission of nociceptive stimuli and also are involved in the release of neurotransmitters important in pain transmission. Ziconotide's therapeutic benefit derives from its potent and selective blockade of neuronal-type voltage-sensitive calcium channels. Blockade of the channels results in suppression of abnormal ectopic discharges from the injury site or the dorsal root ganglia, possibly resulting in decreased neuroplasticity, and decreased synaptic transmission that leads to the generation of chronic pain syndromes. The advantage of ziconotide is that tolerance does not occur, while disadvantages associated with ziconotide are the need for intrathecal administration and significant neurotoxicites associated with its use. When tested in clinical trials, ziconotide has been shown to have synergistic or additive value to the effect of morphine. Ziconotide, formerly known also as SNX- 111, represents a new class of agents, the N-type calcium channel blockers. These may represent another option for patients with refractory pain and refractory pain syndromes.

Analgesics, Non-Narcotic↗

PubMed2004

Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.

Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

Amino Acid Sequence↗

PubMed2006

Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review.

Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of "topically" active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 microg/day) and titrated slowly (increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.

Analgesics, Non-Narcotic↗

PubMed2000

125I-alpha-conotoxin MII identifies a novel nicotinic acetylcholine receptor population in mouse brain.

alpha-Conotoxin MII (CtxMII), a peptide toxin from the venom of the predatory cone snail Conus magus, displays an unusual nicotinic pharmacology. Specific binding of a radioiodinated derivative ((125)I-alpha-CtxMII) was identified in brain region homogenates and tissue sections. Quantitative autoradiography indicated that (125)I-alpha-CtxMII binding sites have an unique pharmacological profile and distribution in mouse brain, being largely confined to the superficial layers of the superior colliculus, nigrostriatal pathway, optic tract, olivary pretectal, and mediolateral and dorsolateral geniculate nuclei. Expression of alpha-CtxMII binding sites in the nigrostriatal pathway, combined with evidence for alpha-CtxMII-sensitivity of nicotine-induced [(3)H]dopamine release in rodent striatal preparations indicates that (125)I-alpha-CtxMII binding nicotinic acetylcholine receptors are likely to be physiologically important. Unlabeled alpha-CtxMII potently (K(i) < 3 nM) competed for a subset of [(3)H]epibatidine binding sites in mouse brain homogenates, but weakly (IC(50) > 10 microM) interacted with (125)I-alpha-bungarotoxin and (-)-[(3)H]nicotine binding sites, confirming this compound's novel nicotinic pharmacology. Quantitative autoradiography revealed that alpha-CtxMII binds with high affinity at a subset of [(3)H]epibatidine binding sites with relatively low cytisine affinity ("cytisine-resistant" sites), resolving [(3)H]epibatidine binding into three different populations, each probably corresponding to a receptor subtype. The majority population seems to correspond to that which binds nicotine and cytisine with high affinity ("cytisine-sensitive" sites). Comparison of the cytisine-resistant population's distribution with that of alpha3 subunit mRNA expression suggests that the fractions both more and less sensitive to alpha-CtxMII probably contain the alpha3 subunit, perhaps in combination with different beta subunits.

Animals↗

PubMed1992

Omega-conotoxin-sensitive calcium channels modulate autonomic neurotransmission in guinea pig airways.

omega-Conotoxin GVIA, a peptide derived from the marine snail Conus geographus, is an antagonist of the neuronal N type voltage-sensitive calcium channels associated with neurotransmitter release. The present study investigated effects of this peptide on neurally mediated responses in airways isolated from the guinea pig to determine whether airway nerves are modulated by omega-conotoxin-sensitive calcium channels. Electrical field stimulation was used to induce neurally mediated tachykininergic excitatory responses in guinea pig bronchus and cholinergic excitatory and nonadrenergic noncholinergic inhibitory responses in guinea pig trachea. Exogenous agonists were administered to induce contractile (acetylcholine, substance P) or relaxation (sodium nitroprusside) responses. Tissues were incubated with omega-conotoxin (1 microM) or its vehicle (10 mM acetic acid) for 30 min before establishing frequency- or concentration-response relationships to the various stimuli. Frequency-response curves for neurally mediated cholinergic, nonadrenergic nocholinergic inhibitory and tachykininergic responses were shifted to the right by omega-conotoxin to a similar extent (4- to 5-fold). omega-Conotoxin had no effect on contractile responses elicited by exogenous acetylcholine or substance P or on relaxations induced by sodium nitroprusside. These findings indicate that neurotransmission in afferent tachykininergic kininergic nerves and in efferent cholinergic excitatory and nonadrenergic noncholinergic inhibitory nerves in the airways is modulated by a prejunctional omega-conotoxin-sensitive mechanism.

Acetylcholine↗

PubMed2006

[New medications; ziconotide].

Ziconotide is a synthetic analogue of a peptide found in the poison of the marine snail Conus magus. Ziconotide blocks N-type calcium channels, which play an important role in the transmission of pain signals in the dorsal ganglia of the spinal cord. The drug is indicated for 'severe chronic pain' and is administered intrathecally.

Analgesics, Non-Narcotic↗

PubMed1987

Mu-conotoxins share a common binding site with tetrodotoxin/saxitoxin on eel electroplax Na channels.

The binding characteristics of conotoxin GIIIA purified from the venom of a marine snail, Conus geographus, with regard to electroplax membranes from Electrophorus electricus were studied using a radiolabeled monopropionyl derivative of the toxin (3H-Pr-CGIIIA). 3H-Pr-CGIIIA bound specifically to a single class of saturable binding sites in electroplax membranes with a dissociation constant of 1.1 +/- 0.2 nM and a maximal binding capacity of 11 +/- 2 pmol/mg of protein. The latter value was similar to the number of specific binding sites (10 +/- 2 pmol/mg of protein) for 3H-lysine-tetrodotoxin (3H-Lys-TTX). Monopropionyl CGIIIA and CGIIIA had similar inhibitory effects on the binding of 3H-Lys-TTX (1 nM) to electroplax membranes with IC50 values of 3.5 and 0.9 nM, respectively. The association and dissociation of 3H-Pr-CGIIIA and electroplax membranes were much slower than those of 3H-Lys-TTX and the membranes. Mu-Conotoxins (CGIIIA and CGIIIB) and guanidinium toxins (TTX and saxitoxin) inhibited 3H-Pr-CGIIIA (1 nM) binding to electroplax membranes with IC50 values of 0.6, 1.1, 7.1, and 2.2 nM, respectively. However, several other kinds of neurotoxins and local anesthetics known to interact with Na channels did not affect 3H-Pr-CGIIIA binding. These findings indicate that mu-conotoxins must be classified in the same group of Na channel inhibitors as guanidinium toxins, since they competed with guanidinium toxins for binding sites on the Na channel. The peptide mu-conotoxins should be useful in studies on the functional and structural domains of Na channel proteins.

Aconitine↗

PubMed1988

Characterization of the omega-conotoxin-binding molecule in rat brain synaptosomes and cultured neurons.

omega-Conotoxin GVIA is a peptide purified from the venom of the marine snail, Conus geographus, that specifically blocks voltage-sensitive calcium channels in neurons. A mono-[125I]iodo-omega-conotoxin was prepared and specific binding to both rat brain synaptosomal membranes and cultured neurons was detected. The interaction was irreversible and the association kinetic constant k was measured at 5-7 X 10(6) M-1 s-1 in synaptosomes and at 2-4 X 10(6) M-1 s-1 on intact neurons. The binding site capacities were 650 and 60 fmol/mg of protein, respectively. No competition was detected with other calcium channel blockers or with toxins acting on Na+ or K+ channels but the binding was lowered by the divalent cations Co2+ and Ca2+. Photoaffinity experiments specifically labeled a single component with an apparent Mr of 222,000 +/- 7,000 in brain synaptosomes and 245,000-300,000 in cultured embryonic neurons.

Animals↗

PubMed1985

Postsynaptic block of frog neuromuscular transmission by conotoxin GI.

Conotoxin GI, a peptide neurotoxin contained in the venom of the marine snail Conus geographus, was applied to the cutaneous pectoris muscle of the frog, and the effects on the postsynaptic response to acetylcholine were examined. Conotoxin GI reversibly blocked nerve-evoked muscle contractions at concentrations greater than or equal to 3 to 4 microM. Micromolar concentrations of conotoxin GI significantly reduced the amplitude of miniature endplate potentials and membrane depolarizations produced by ionophoretic application of acetylcholine, suggesting that the toxin reduced the postsynaptic sensitivity to acetylcholine. The reduction in the sensitivity of the muscle to acetylcholine was not due to changes in muscle fiber resting membrane potential or input resistance. Conotoxin GI reduced the amplitudes but did not affect the rates of decay of focal, extracellularly recorded endplate currents or miniature endplate currents, suggesting that the toxin did not affect the lifetime of ion channels opened by acetylcholine. Miniature endplate currents decay five to six times more slowly than normal when acetylcholinesterase is blocked with neostigmine methyl sulfate due to repeated binding of acetylcholine to receptors as it diffuses from the synaptic cleft. Conotoxin GI reduced the amplitude and increased the rate of decay of miniature endplate currents recorded in the presence of neostigmine methyl sulfate, suggesting that the toxin reduced the binding of acetylcholine to endplate receptors. These results are consistent with the hypothesis that conotoxin GI blocks neuromuscular transmission at the frog endplate by reducing the binding of acetylcholine to receptors.

Acetylcholine↗

PubMed2005

Putative gamma-conotoxins in vermivorous cone snails: the case of Conus delessertii.

Peptide de7a was purified from the venom of Conus delessertii, a vermivorous cone snail collected in the Yucatan Channel, Mexico. Its amino acid sequence was determined by automatic Edman degradation after reduction and alkylation. The sequence shows six Cys residues arranged in the pattern that defines the O-superfamily of conotoxins, and several post-translationally modified residues. The determination of its molecular mass by means of laser desorption ionization time-of-flight mass spectrometry (average mass, 3170.0 Da) confirmed the chemical data and suggested amidation of the C-terminus. The primary structure (ACKOKNNLCAITgammaMAgammaCCSGFCLIYRCS*; O, hydroxyproline; gamma, gamma-carboxyglutamate; *, amidated C-terminus; calculated average mass, 3169.66 Da) of de7a contains a motif (gammaCCS) that has previously only been found in two other toxins, both from molluscivorous cone snails: TxVIIA from Conus textile and gamma-PnVIIA from Conus pennaceus. These toxins cause depolarization and increased firing of action potentials in molluscan neuronal systems, and toxin gamma-PnVIIA has been shown to act as an agonist of neuronal pacemaker cation currents. The similarities to toxins TxVIIA and gamma-PnVIIA suggest that peptide de7a might also affect voltage-gated nonspecific cation pacemaker channels.

Amino Acid Sequence↗

PubMed1999

Molecular genetics of ecological diversification: duplication and rapid evolution of toxin genes of the venomous gastropod Conus.

Predatory snails in the marine gastropod genus Conus stun prey by injecting a complex mixture of peptide neurotoxins. These conotoxins are associated with trophic diversification and block a diverse array of ion channels and neuronal receptors in prey species, but the evolutionary genesis of this functional diversity is unknown. Here we show that conotoxins with little amino acid similarity are in fact products of recently diverged loci that are rapidly evolving by strong positive selection in the vermivorous cone, Conus abbreviatus, and that the rate of conotoxin evolution is higher than that of most other known proteins. Gene duplication and diversifying selection result in the formation of functionally variable conotoxins that are linked to ecological diversification and evolutionary success of this genus.

Amino Acid Sequence↗