Potassium channels mechanisms

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

In addition to the mechanism involving cycHc AMP, nonsugar sweeteners, eg, saccharin and a guanidine-type sweetener, have been found to enhance the production of another second messenger, inositol 1,4,5-trisphosphate (IP3), causing the closure of potassium channels and the release of... 

Additional cellular events linked to the activity of blood pressure regulating substances involve membrane sodium transport mechanisms Na+/K.+ ATPase Na+fLi countertransport Na+ -H exchange Na+-Ca2+ exchange Na+-K+ 2C1 transport passive Na+ transport potassium channels cell volume and intracellular pH changes and calcium channels. 

Brown, DA (2000) The acid test for resting potassium channels. Curr. Biol. 10 R456-R459. Dolphin, AC (1998) Mechanisms of modulation of voltage-dependent calcium channels by G proteins. J. Physiol. 506 3-11. 

The mu, delta and kappa opioid receptors are coupled to G° and G proteins and the inhibitory actions of the opioids occur from the closing of calcium channels (in the case of the K receptor) and the opening of potassium channels (for /i, d and ORL-1). These actions result in either reductions in transmitter release or depression of neuronal excitability depending on the pre- or postsynaptic location of the receptors. Excitatory effects can also occur via indirect mechanisms such as disinhibition, which have been reported in the substantia gelatinosa and the hippocampus. Flere, the activation of opioid receptors on GABA neurons results in removal of GABA-mediated inhibition and so leads to facilitation. 

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron...

Some of the most revealing studies of partial agonism (including Stephenson s seminal work) have been done with tissues in which G-proteins (see Chapters 2 and 7) provide the link between receptor activation and initiation of the response. In contrast to the situation with fast receptors with intrinsic ion channels (see above), it is not yet possible to observe the activity of individual G-protein-coupled receptors (with the potential exception of some that are linked to potassium channels) however, enough is known to show that the mechanisms are complex. The interpretation of differences in efficacy for agonists acting at such receptors is correspondingly less certain. 

Jiang, Y., Lee, A., Chen, J. et al. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515-522, 2002. 

Hoshi, T., Zagotta, W. and Aldrich, R. W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250,533-538,1990. 

Several studies support the notion that the basic mechanism by which many drugs prolong the QT interval is related to blockade of potassium currents. For instance, several antihistamines, antibacterial macrolides, fluoroquinolones and antipsychotics were shown to inhibit the rapid component of the delayed rectifier K+ current (fKr) in electrophysiological studies and to block potassium channels encoded by hERG [37-42]. 

Zhang, S., Zhou, Z., Gong, Q., Makielski, J.C. and January, C.T. (1999) Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circulation Research, 84, 989-998. 

The cellular mechanism of cannabinoid analgesia is uncertain. Although cAMP and adenylate cyclase mediate other effects of cannabinoids, they do not appear to be involved in cannabinoid-induced analgesia (Cook et al. 1995). Instead, other mechanisms such as cannabinoid receptor-coupled calcium or potassium channels may be responsible. 

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