Voltage Sensitive Potassium Channels

Opening of voltage-sensitive potassium channels and the related calcium-dependent potassium channels is responsible for the repolarizing phase of the action potential. Especially, the calcium-dependent potassium channels remain active even after return of the membrane potential to its baseline, and are the basis of the often long-lasting afterhyperpolarization, which is associated with a significant decrease in excitability following the action potential. Eighteen distinct voltage-sensitive potassium channels belonging to four families have been cloned. Compared to sodium channels, the structure-function relationship of potassium channels is more complex because four proteins combine into a homo- or hetero-oligomeric complex to form the channel pore (87,88). This picture is further confounded by associated P subunits that modulate channels properties. The expression pattern of potassium channel provides some clues about their role in the sensation of pain with one channel subunit, Kv1.4, preferentially expressed in primary sensory neurons that are positive for neurochemical markers associated with nociception (89). More direct information comes from experiments with knockout animals. Consistent with the role of potassium channels in repolarization, neurons lacking Kv1.1, a rapidly inactivating potassium channel, respond with prolonged bursts of action potentials when stimulated (90). Such enhanced responses may contribute to the hyperalgesia seen in Kv1.1-deficient mice during heat stimuli and inflammation (91).

Same as VSSC, potassium channels are modulated by inflammatory mediators. However, while prostaglandins enhance sodium channel activity, they decrease potassium currents, both of which will increase excitability (92). In addition to this rapid modulation through inflammatory mediators, experimental models of visceral inflammation and pain are associated with a lasting decrease in potassium currents due to changes in channel expression (Fig. 6). This change primarily involves the rapidly activating and inactivating potassium current (A current) (50,64,93). Pharmacologic inhibition of this A current significantly increases excitability. Consistent with these results, neurons obtained from animals with visceral inflammation showed a decrease in the transient potassium current, had a lower

Gastric ulcer

Figure 6 Potassium currents in visceral inflammation. (A) Superimposed current tracings triggered by stepwise depolarization of a gastric dorsal root ganglion neuron show transient and sustained potassium currents. (B) Ulceration decreases the transient current in gastric nodose and dorsal root ganglion neurons. Abbreviations: NG, nodose ganglion; DRG, dorsal root ganglion.

threshold for action potential generation, and responded with higher spike frequencies during prolonged stimulation (57).

Several potassium channels also contribute to the resting membrane potential. Modulation or loss of these channels increases excitability and is associated with seizures and cardiac arrhythmias, disorders associated with an increase in excitability (94). While hyper-excitability is also the hallmark of peripheral sensitization, the role of these channels in pain is less clear. Recently, KCNQ2 and KCNQ3 channels have been identified in primary sensory neurons. Pharmacologic activators of these channels blunted responses to afferent stimulation and inhibited pain behavior during chronic inflammation (95). While still untested in the clinical arena, the use of such potassium channel openers may provide novel options for analgesic therapy.

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