Voltage-sensitive K channels

Sodium channels open more rapidly than K+ channels because they are more voltage sensitive and a small depolarization is sufficient to open them. Larger changes in membrane potential associated with further cell excitation are required to open the less voltage-sensitive K+ channels. Therefore, the increase in the permeability of K+ ions occurs later than that of Na+ ions. This is functionally significant because if both types of ion channels opened concurrently, the change in membrane potential that would occur due to Na+ ion influx would be cancelled out by K+ ion efflux and the action potential could not be generated. 

Aminopyridine is used broadly as an avicide. It is classified as a restricted use pesticide by the US Environmental Protection Agency. The compound is also being developed for clinical human application in the treatment of certain nerve conduction disorders, and it is used in experimental laboratory settings as an in vitro antagonist of voltage sensitive K" " channels. 

The mechanism of 4-aminopyridine toxicity is due to the direct actions of the compound as a blocker of voltage-sensitive K" " channels. At toxic doses, the chemical disrupts normal action potential conduction and nonselectively enhances neurotransmitter release. Because 4-aminopyridine blocks voltage-sensitive K+ channels on neurons, it has the capacity to enhance action potential conduction in demyelinated tissue with therapeutically beneficial results. Toward this end, a compound (fampridine) is in development... 

It is now established that in colliculi, hippocampal and cortical neurons, 5-HT4-Rs are positively coupled to AC [2, 5, 62]. In colliculi neurons, 5-HT4-R-mediated c-AMP accumulation leads to blockade of voltage-sensitive K channels via activation of a c-AMP-dependent protein kinase (PKA) [63]. Figure 6 indicates that a very brief stimulation (1 min in this figure but indeed a few seconds in most experiments) is sufficient to induce a slowly developing (15-20 min) inhibition of K currents. Once established, this inhibition is very long lasting at least 2 hours... 

Tsang SY, Yao X, Essin K, Wong CM, Chan FL, Gollasch M, Huang Y (2004) Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels. Stroke 35(7) 1709-1714... 

Richardson, P. J., Mizuguchi, K., Jackson, A. P. Beta3 an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channels gating with distinct kinetics, Proc. Natl. Acad. Sci. USA 2000, 97, 2308-2313. 

Ekinci, F. J., Malik, K. U., and Shea, T. B. (1999). Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem 274, 30322-30327. 

Ueda, K., Shinohara, S., Yagami, T., Asakura, K., and Kawasaki, K. (1997). Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels a possible involvement of free radicals. J Neurochem 68, 265—271. 

Coffey ET, Sihra TS, Nicholls DG et al (1994b) Phosphorylation of synapsin I and MARCKS in nerve terminals is mediated by Ca2+ entry via an Aga-GI sensitive Ca2+ channel which is coupled to glutamate exocytosis. FEBS Lett 353 264-8 Colby KA, Blaustein MP (1988) Inhibition of voltage-gated K channels in synaptosomes by sn-1,2-dioctanoylglycerol, an activator of protein kinase C. J Neurosci 8 4685-92... 

Fig. 3.27. Photoaffinity reagents made by attaching photoactivatabie groups to readily available ligands, a Cardiac glycoside derivative for reaction with Na,K-ATPase. The reactive secondary hydroxyl of cymarin was reacted with ethyldiazomalonyl chloride (Ruoho and Kyte, 1974, 1977). b Tetrodotoxin derivative for reaction with the voltage-sensitive Na-channel. Tetrodotoxin was oxidised with periodate to form a ketone which was reacted with an azidoarylhydrazide (Chicheportiche et al., 1979).

Nielsen, K.J., Schroeder, T., Lewis, R. (2000). Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels. J. Mol. Recognit. 13 55-70. 

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