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The Voltage-gated Calcium Channel and Omega-Conotoxins

The omega-conotoxins are peptides of 24-30 amino acids in length with three disulfide bonds. The best defined are omega-conotoxin GVIA from Conus geographus, omega conotoxins MVIIA, MVIIIV and MVIID from Conus magus, omega CNVIIA from Conus consors and omega conotoxin CVID from the venom of Conus catus.

They are known as 'shaker peptides' as they induce persistent tremors in mice when injected intracerebally. GVIA , GVIB and GVIC all block the neuromuscular junction of skeletal muscle, and act by blocking calcium channels without interfering with cellular action potentials. Differential effects are observed upon the application of GVIA - it appears that of the three types of calcium channel, the toxin will block the L and N type in neurons, but only has effect on the N type in muscle. This channel subtype specific response may be useful in the identification and manipulation of calcium channels.

  • In mammalian systems, omega GVIA and omega MVIIA are remarkably specific for voltage-gated calcium channels that contain the alpha 1A subunits. Since calcium channels present at presynaptic termini generally belong to the classes discussed above, omega conotoxins have become widely used tools for blocking synaptic transmission and studying synapses.
  • Another member of the family, omega conotoxin MVIIA is an N type calcium channel blocker and is reported to be 100-1000 fold more potent than morphine as an analgesic but is not addictive. This conotoxin (also known as SNX-111) is undergoing stage III clinical trials in the USA as a treatment for intractible pain.
  • David Goldenberg's laboratory at the University of Utah has examined the in vitro refolding reactions of several omega conotoxins and has in addition studied the folding of two putative precursor forms of one peptide, omega-MVIIA. This work including ChemChime molecular graphics of omega conotoxin MVIIA.
  • Whereas the omega conotoxin MVIIA blocks neuronal N-type calcium channels, a newly discovered toxin from the venom of a carnivorous spider venom, blocks R-type calcium channels. The compound, known as SNX-482 was isolated from the venom of the African tarantula, Hysterocrates gigas, and is the first R-type calcium channel blocker described. The R-type calcium channel is believed to play an important role in the body's natural communication network where it contributes to the regulation of brain function. Details concerning its discovery were presented by researchers from Neurex Corporation at the 27th Annual Meeting of the Society for Neuroscience in New Orleans, November 1997.

    Voltage-gated Calcium ion channels update

  • Ca2+ channels have been classified pharmacologically and biophysically. The channels are designated L-, T-, N-, P-, Q- and R-type. Each channel has different voltage ranges and rates for activation and inactivation.
  • The N-type typically are inactivated more rapidly then the L-, P- and Q-types.
  • The N-type channels are irreversibly blocked by the snail toxin omega-conotoxin GVIA and are thought to be responsible for neurotransmitter release at synaptic junctions. Another snail toxin, omega-conotoxin MVIIC, inhibits N-, P- and Q-type currents.
  • Each channel type has been cloned and is composed of a large a1 subunit in combination with one or more smaller accessory subunits
  • The subunit composition of native Ca2+ channels is further complicated by the diversity of the auxiliary subunits alpha2(A-E)/delta, beta1-4 and gamma- described to date. The functional roles of all these subunits are not fully understood.
  • Neurotransmitter release from preganglionic parasympathetic neurons is resistant to inhibition by selective antagonists of L-, N-, P/Q-, R- and T-type calcium channels. omega-conotoxin CVID from Conus catus inhibits a pharmacologically distinct voltage-sensitive calcium channel involved in neurotransmitter release (Adams et al 2002), whereas omega-conotoxin MVIIA had no effect. Given that relatively small differences in the sequence of the N-type calcium channel alpha(1B) subunit can influence omega-conotoxin access (Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P. and Zamponi, G. W. (2001) J. Biol. Chem. 276,15728-15735), it has been proposed (Adams et al 2002) that the calcium channel in preganglionic nerve terminals targeted by CVID is a N-type (Ca(v)2.2) calcium channel variant.

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CG and BGL, December-97. Updated Feb. 2004

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