Ciguatoxins: Cyclic polyether modulators of voltage-gated Iion channel function

Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na+-dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.

Mutations within the selectivity filter of the NMDA receptor-channel influence voltage dependent block by 5-hydroxytryptamine

Background and purpose: Voltage-dependent block by Mg2+ is a cardinal feature of NMDA receptors which acts as a coincidence detector to prevent the receptor from over-activation. Inhibition of NMDA receptor currents by 5-hydroxytryptamine (5-HT) indicated that 5-HT, similar to Mg2+, binds within the membrane electric field. In the present study, we assessed whether point mutations of critical asparagine residues located within the selectivity filter of NR1 and NR2A subunits of NMDA receptor-channel affect voltage-dependent block by 5-HT. Experimental approach: The mode of action of 5-HT and Mg2+ on wild-type and mutated NMDA receptor-channels expressed in Xenopus oocytes was investigated using the two-electrode voltage clamp recording technique. Key results: The mutation within the NR1 subunit NR1(N0S or N0Q) strongly reduced the voltage dependent block by 5-HT and increased the IC50. The corresponding mutations within the NR2 subunits NR2A(N0Q or N + 1Q) reduced the block by 5-HT to a lesser extent. This is in contrast to the block produced by external Mg2+ where a substitution at the NR2A(N0) and NR2A(N + 1) sites but not at the NR1(N0) site significantly reduced Mg2+ block. Conclusion and implications: The block of NMDA receptor-channels by 5-HT depends on the NR1-subunit asparagine residue and to a lesser extent on the NR2A-subunit asparagine residues. These data suggest that the interaction of 5-HT with functionally important residues in a narrow constriction of the pore of the NMDA receptor-channel provides a significant barrier to ionic fluxes through the open channel due to energetic factors governed by chemical properties of the binding site and the electric field.

Neuronal voltage-gated sodium channel subtypes: Key roles in inflammatory and neuropathic pain

Voltage-gated sodium channels (VGSCs) play an important role in neuronal excitability. Regulation of VGSC activity is a complex phenomenon that occurs at multiple levels in the cell, including transcriptional regulation, post-translational modification and membrane insertion and retrieval. Multiple VGSC subtypes exist that vary in their biophysical and pharmacological properties and tissue distribution. Any alteration of the VGSC subtype profile of a neuron or the mechanisms that regulate VGSC activity can cause significant changes in neuronal excitability. Inflammatory and neuropathic pain states are characterised by alterations in VGSC subtype composition and activity in sensory neurons. This review focuses on the VGSC subtypes involved in such pain states. (c) 2006 Elsevier Ltd. All rights reserved.

On the chaotic instability of a nonsliding liquid-filled top with a small spheroidal base via Melnikov-Holmes-Marsden integrals

Chaotic orientations of a top containing a fluid filled cavity are investigated analytically and numerically under small perturbations. The top spins and rolls in nonsliding contact with a rough horizontal plane and the fluid in the ellipsoidal shaped cavity is considered to be ideal and describable by finite degrees of freedom. A Hamiltonian structure is established to facilitate the application of Melnikov-Holmes-Marsden (MHM) integrals. In particular, chaotic motion of the liquid-filled top is identified to be arisen from the transversal intersections between the stable and unstable manifolds of an approximated, disturbed flow of the liquid-filled top via the MHM integrals. The developed analytical criteria are crosschecked with numerical simulations via the 4th Runge-Kutta algorithms with adaptive time steps.

Thiamin nutrition and catalysis-induced instability of thiamin diphosphate

Thiamin (vitamin B1) is required in animal diets because it is the precursor of the enzyme cofactor, thiamin diphosphate. Unlike other B vitamins, the dietary thiamin requirement is proportional to non-fat energy intake but there is no obvious biochemical reason for this relationship. In the present communication we show for two enzymes that the cofactor undergoes a slow destruction during catalysis, which may explain the interdependence of thiamin and energy intakes.

A unified friction description and its application to the simulation of frictional instability using the finite element method

This article first summarizes some available experimental results on the frictional behaviour of contact interfaces, and briefly recalls typical frictional experiments and relationships, which are applicable for rock mechanics, and then a unified description is obtained to describe the entire frictional behaviour. It is formulated based on the experimental results and applied with a stick and slip decomposition algorithm to describe the stick-slip instability phenomena, which can describe the effects observed in rock experiments without using the so-called state variable, thus avoiding related numerical difficulties. This has been implemented to our finite element code, which uses the node-to-point contact element strategy proposed by the authors to handle the frictional contact between multiple finite-deformation bodies with stick and finite frictional slip, and applied here to simulate the frictional behaviour of rocks to show its usefulness and efficiency.

Evidence for microsatellite instability in bilateral breast carcinomas

The molecular pathogenesis of various categories of breast cancer (BC) has been well described, but surprisingly few reports have appeared on analysis of somatic mutations in bilateral BC. We have performed a polymerase chain reaction (PCR)-driven investigation of chromosomal regions showing common loss of heterozygosity (LOH) in 23 cases (46 rumors) from patients diagnosed with bilateral BC, LOH was observed in 15/46 (33%) informative tumors for chromosome 1p, 5/32 (16%) for 5q, 12/44 (27%) for 11q, 15/40 (38%) for 13q and 4/24 (17%) for 17p. These values are within the range of interlaboratory variations reported fur unilateral BC, There was no strong evidence for concordance of LOH within the same patient for any of the chromosomal loci tested. Atypical for breast carcinomas, 7/46 (15%) turners accumulated a high frequency (ranging from 11 to 29%) of shortened dinucleotide CA repeats, implying microsatellite instability (MI). Further analysis with the highly informative BAT-26 marker allowed for the classification of two of these tumors as having a replication error positive (RER+/MSI-H) phenotype, whereas the remaining five carcinomas harbored so-called borderline MI. Thus an involvement of both RER+ and borderline MI appears to be a distinct feature of bilateral breast carcinomas compared to unilateral lesions. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Distance measurement using the change in junction voltage across a laser diode due to the self-mixing effect

Conventional detection scheme for self-mixing sensors uses an integrated photodiode within the laser package to monitor the self mixing signal. This arrangement can be simplified by directly obtaining the self-mixing signals across the laser diode itself and omitting the photodiode. This work reports on a Vertical-Cavity Surface-Emitting Laser (VCSEL) based selfmixing sensor using the laser junction voltage to obtain the selfmixing signal. We show that the same information can be obtained with only minor changes to the extraction circuitry leading to potential cost saving with reductions in component costs and complexity and significant increase in bandwidth favoring high speed modulation. Experiments using both photo current and voltage detection were carried out and the results obtained show good agreement with the theory.