Snake venom three-finger toxins and their potential in drug development targeting cardiovascular diseases

Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.

Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions.