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Issue No. 17

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Ion Channels in Cancer

Ion channels have long been known to be involved in the regulation of a variety of biological functions ranging from the control of cell excitability to the regulation of cell volume and proliferation. Because of the ubiquitous presence of ion channels in virtually all cells and their critical involvement in diverse biological functions, it came as no surprise when several human and animal diseases were attributed to defects in ion channel function. Indeed, the term channelopathies was coined to describe the ever growing number of diseases associated with ion channel function. Channelopathies have been recognized in the context of conditions as diverse as epilepsy1, cardiac arrhythmias2, skeletal muscle disorders3 and diabetes4.

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Large Conductance Ca2+-Dependent K+ (BKCa) Channels

Ca2+ dependent K+ (KCa) channels are divided according to biophysical properties and gene homology into two main groups. KCa were first divided according to their single channel conductance, which represents the speed by which the K+ passes via the open channel. The first group consists of small and intermediate conductance channels (SK and IK respectively, the KCNN gene family). The second group is comprised of large/big conductance channels (called BKCa or maxiK, encoded by the slo or KCNMA1 gene)1.

BKCa channels are both voltage and [Ca2+]in dependent and their response to both signals results in extensive K+ efflux (due to their large single channel conductance) and

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Na+/H+ Exchanger Regulatory Factor-1 (NHERF-1): A PDZ-Domain Containing Protein Adaptor

The Na+/H+ exchanger regulatory factor (NHERF-1 or EBP-50) is a 55 kD cytoplasmic protein adaptor that recruits a wide variety of cellular proteins. Many of the interacting proteins do so through the two tandem PDZ domains (protein-binding domains conserved in the mammalian synaptic protein PSD-95/DlgA/ZO-1) and the C-terminal ERM (ezrin, radixin, moesin) binding region.

NHERF-1 was first identified as an adaptor necessary for the function of the Na+/H+ exchanger isoform 3(NHE3) in renal apical cells1. Since then it has been identified in cells of epithelial origin in several tissues such as gastrointestinal and lung. NHERF-1 has been shown to interact with a growing number of proteins including ion channels

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Voltage-Dependent K+ (KV) Channels: A Large and Diverse Family of Membrane Voltage Regulators

K+ selective channels are some of the most widespread ion trafficking molecules in living organisms, with more than 70 genes encoding different K+ channels in humans.

K+ channels are gated by a variety of factors: voltage, cyclic nucleotides, ATP, Ca2+, Na+ and G-proteins, which may act singly or in combination. Therefore, many of these channels serve and operate as sensors for the cell’s metabolic state. In addition, K+ channels contribute to maintenance of a cell’s resting membrane potential and fine-tuning excitability in neurons, heart and muscle, mainly by defining the action potential duration and the intervals between them.

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The Ionotropic GABAA Receptor

GABA (g-aminobutiric acid) is the major inhibitory neurotransmitter in the brain. Its production, release, reuptake and metabolism occur in the nervous system.1

The GABA transmitter interacts with two major types of receptors: ionotropic GABAA (GABAAR) and the metabotropic GABAB receptors. The GABAAR belong to the ligand-gated ion channel superfamily.2

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α-Latrotoxin: A Molecular Tool for Induction of Neurotransmitter Release

α-Latrotoxin is a 130 kD protein toxin from the black widow spider venom and is the only protein in the venom that affects mammals (for reviews see references 1,2).

Application of the toxin to presynaptic preparations induces, after a delay, a huge increase in spontaneous neurotransmitter release, which can be evaluated by measuring the postsynaptic response in the form of miniature end plate potentials.

It is widely used to induce and study neurotransmitter release (see Table 1), but the molecular mechanism of its action is not fully determined.

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Role of Neurotrophins in Synapse Formation

The neurotrophins (“neuro” means nerve and “trophe” means nutrient)1 are a family of soluble, basic growth factors which regulate neuronal development, maintenance, survival and death in the central and peripheral nervous systems2. They include NGF, the first member of the family to be discovered, BDNF, NT3 and NT4/5. Their actions are mediated by two types of receptors: the Trk family, which matches each neurotrophin to its own receptor3, and p75NTR which is a universal neurotrophin receptor4.

The neurotrophins have been shown to affect dendritic and axonal growth5, efficacy of synaptic transmission6. maturation of synaptic contacts, density of synaptic

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The Purinergic P2X Receptors

ATP has been identified as an excitatory neurotransmitter and neuromodulator during physiological processes. The released ATP activates a class of receptors named purinergic receptors: the metabotropic P2Y receptors and the ionotropic P2X receptors1,2. The P2X receptors belong to the ligand-gated ion channel family and are responsible for fast excitatory neurotransmission and are involved in diseases of the nervous system.

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T-type CaV Channels

Voltage-dependent Ca2+ (CaV) channels form an important route for Ca2+ entry into cells, upon deviations from the cell’s resting membrane potential. Functionally, CaV channels are divided into Low Voltage-Activated (LVA) and High Voltage-Activated (HVA) channels1.

This functional division implies that cells respond differentially to small or large depolarization of the plasma membrane, activating two different classes of CaV channels, which conduct the Ca2+ inflow with different characteristics. T-type currents are carried out via channel proteins encoded by three genes that compose a subfamily within the CaV channels family (see Table 1)2-4. Several biophysical properties distinguish LVA from HVA CaV channels. The “T” stands for transient, resulting from the strong

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The Purinergic P2Y Receptors

P2 receptors mediate the actions of the extracellular nucleotides (ATP, ADP, UTP, UDP) and regulate several physiologic responses, among them, cardiac function, platelet aggregation, and SMC proliferation1. The metabotropic P2Y receptors belong to the G-protein-coupled receptor (GPCR) super family.  There are currently six functional mammalian P2Y receptors: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11 and P2Y12 which differ in their selectivity for adenine and uracil nucleotides: ATP (P2Y11 receptor), ADP (P2Y1, P2Y12 receptors), UTP (P2Y4 receptor). The response of P2Y4 to ATP is species-dependent.  UDP activates the P2Y6 receptor. The P2Y2 receptor is equipotently activated by ATP and UTP. Most P2Y receptors (with the exception of P2Y11 and P2Y12) are coupled to the activation of phospholipase C (PLC), leading to the formation of

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