Cellular excitable

K Channels belong to a class of membrane proteins that form highly K-selective pores in membranes. All known K Channels are composed of several (usually four) pore forming alpha subunits and auxiliary beta subunits. K Channels play an essential role in cellular excitability, being involved in repolarization of Action Potentials and setting the cell resting potential as well as contributing to potassium homeostasis. 

Recent drug development studies have centered on the capacity of known antiepileptic drugs (AEDs) to interact with ion channels, and it is now established that several agents appear to be exerting their effects primarily by inhibiting ion channels. Modulation of neuronal sodium channels decreases cellular excitability and the propagation of nerve impulses. Inhibition of sodium channels appears to be a major component of the mechanism of action of several anticonvulsant drugs. 

The main effects of BZs occur via positive allosteric modulation. The BZs and GABA bind to separate sites on the GABAa receptor complex. When a BZ occupies the BZ receptor, GABA s ability to open the chloride channels increases. With greater opening of the chloride channel, cellular excitability decreases (Ballenger, 1995). The final result of this decreased cellular excitability is widespread because of the extensive inhibitory role of GABA in the CNS. As a result, BZs may alter the turnover of neurotransmitters such as norepinephrine and serotonin (5-hydroxytryptamine [5-HT]). 

In the spinal cord, a2-agonists act on receptors located on the terminals of primary afferent fibers in the dorsal horn substantia gelatinosa to reduce nociceptive transmission by inhibiting the release of glutamate and substance P (Collin et al., 1994 Hamalainen and Pertovaara, 1995) (see Fig. 2). These receptors appear to be primarily of the a2A subtype which is negatively coupled to adenylate cyclase (Lakhlani et al., 1997 see Millan, 1999 but see Sawamura et al., 2000, and references therein for a discussion of the possible involvement of other a2-receptor subtypes in antinociception). Like activation of p-opioid receptors, the activation of a2-receptors increases the potassium conductance of the cells bearing these receptors, thus reducing cellular excitability. 

Opioids including morphine acting on metabotrobic pi—opioid receptors produce their inhibitory effect on cellular excitability in part by activation of Gj/0-protein-coupled K+ channels thereby hyperpolarizing the membrane potential (Williams et al., 1982 Han et al.,... 

A class of cardiac potassium channels operates in smooth and skeletal muscle, brain, and pancreatic cells. Potassium channels are activated when intracellular ATP levels decrease, and are an important link between the cellular excitability and the metabolic status of the cell. The ratio of ATP/ADP, pH, lactate, and divalent cations determines and modulates the channel activity. The opening of the potassium channels leads to membrane hyperpolarization and a potential decrease as the potassium ions flow out of the cell. Since phosphorylation changes the activity of potassium channels, it modulates cellular excitability. 

The third class of cellular excitability proteins are receptors that are coupled to intracellular second messenger systems through a class of protein complexes known as G proteins, as discussed below. These... 

Excessive calcium entry into depolarized neurons contributes significantly to neuronal injury. Voltage-sensitive calcium channels (VSCCs) regulate, among other functions, cellular excitability and neurosecretory activity, functions implicit in epileptogenic events... 

A decrease below the threshold Pq, normally close to 50 Torr, in glomus cells of the carotid body or in the neonatal ductus arteriosus results in an inhibition of the tonic K current. Such oxygen-regulated inhibition of K+ channels, which may be mediated by mitochondria-derived hydrogen peroxide (Archer et al., 2004), results in an increase in cellular excitability, increased Ca + influx, and a resultant increase in the level of Ca + in the cytosol (reviewed by Lopez-Barneo et al., 1999). 

Cellular Calcium Regulation Calciiun plays critical roles in cellular communication and regulation. The normally very low resting free ionized concentration of Ca is maintained by a variety of ion channels, pumps, and intracellular storage processes. The elevation of intracellular Ca levels during cell stimulation serves to couple information with cellular response -stimulus-response coupling. The control of Ca " homeostasis represents, therefore, a potentially powerful control of cellular excitability and response [ 5 ]. 

Prior to cellular excitation, an electrical gradient exists between the inside and the outside of the cell membrane. At this time, the cell is polarized. In atrial and ventricular conducting tissue, the intracellular space is about 80 to 90 mV negative with respect to the extracellular environment. The electrical gradient just prior to excitation is referred to as resting membrane potential (RMP) and is the result of differences in ion concentrations between the inside and the outside of the cell. At RMP, the cell is polarized primarily by the action of active membrane ion pumps, the most notable of these being the sodium-potassium pump. For example, this specific pump (in addition to other systems) attempts to maintain the intracellular sodium concentration at 5-15 mEq/L and the extracellular sodium concentration at 135-142 mEq/L and the intracellular potassium concentration at 135-140 mEq/L and the extracellular potassium concentration at 3-5 mEq/L. RMP can be calculated by using the Nemst equation ... 

The development of the concept of ionic channel started with the realisation by Bernstein that cellular excitability was a property of the membrane. The starting point at the experimental level was the observation by Cole and Curtis that, concomitant with a propagated electrical impulse (manifestation of cellular electrical excitability) in the squid giant nerve fibre, a decrease in the electrical resistance took place with no detectable change in the membrane capacitance. This result lent strong support to Bernstein s concept and clearly indicated that the most plastic components of the axolemma, the proteins, underwent structural transitions leading to a transient increase in ionic fluxes. 

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