Calcium-activated potassium channels: implications for aging and age-related neurodegeneration.

Population aging, as well as the handling of age-associated diseases, is a worldwide increasing concern. Among them, Alzheimer's disease stands out as the major cause of dementia culminating in full dependence on other people for basic functions. However, despite numerous efforts, in the last decades, there was no new approved therapeutic drug for the treatment of the disease. Calcium-activated potassium channels have emerged as a potential tool for neuronal protection by modulating intracellular calcium signaling. Their subcellular localization is determinant of their functional effects. When located on the plasma membrane of neuronal cells, they can modulate synaptic function, while their activation at the inner mitochondrial membrane has a neuroprotective potential via the attenuation of mitochondrial reactive oxygen species in conditions of oxidative stress. Here we review the dual role of these channels in the aging phenotype and Alzheimer's disease pathology and discuss their potential use as a therapeutic tool.

Airway smooth muscle relaxation induced by 5-HT(2A) receptors: role of Na(+)/K(+)-ATPase pump and Ca(2+)-activated K(+) channels.

AIMS: Although 5-hydroxytryptamine (5-HT) contracts airway smooth muscle in many mammalian species, in guinea pig and human airways 5-HT causes a contraction followed by relaxation. This study explored potential mechanisms involved in the relaxation induced by 5-HT. MAIN METHODS: Using organ baths, patch clamp, and intracellular Ca(2+) measurement techniques, the effect of 5-HT on guinea pig airway smooth muscle was studied. KEY FINDINGS: A wide range of 5-HT concentrations caused a biphasic response of tracheal rings. Response to 32 microM 5-HT was notably reduced by either tropisetron or methiothepin, and almost abolished by their combination. Incubation with 10 nM ketanserin significantly prevented the relaxing phase. Likewise, incubation with 100 nM charybdotoxin or 320 nM iberiotoxin and at less extent with 10 microM ouabain caused a significant reduction of the relaxing phase induced by 5-HT. Propranolol, L-NAME and 5-HT(1A), 5-HT(1B)/5-HT(1D) and 5-HT(2B) receptors antagonist did not modify this relaxation. Tracheas from sensitized animals displayed reduced relaxation as compared with controls. In tracheas precontracted with histamine, a concentration response curve to 5-HT (32, 100 and 320 microM) induced relaxation and this effect was abolished by charybdotoxin, iberiotoxin or ketanserin. In single myocytes, 5-HT in the presence of 3 mM 4-AP notably increased the K(+) currents (I(K(Ca))), and they were completely abolished by charybdotoxin, iberiotoxin or ketanserin. SIGNIFICANCE: During the relaxation induced by 5-HT two major mechanisms seem to be involved: stimulation of the Na(+)/K(+)-ATPase pump, and increasing activity of the high-conductance Ca(2+)-activated K(+) channels, probably via 5-HT(2A) receptors.

Effects of NS1608, a BK(Ca) channel agonist, on the contractility of guinea-pig urinary bladder in vitro.

1. The functional effects of NS1608 ((N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl)urea), an opener of the large conductance, Ca2+-activated K+ (BK(Ca)) channel, on the contractility of guinea-pig urinary bladder muscle are described. 2. NS1608 (0.3-30 microM) had no significant effect on the integrated myogenic activity (tension integral) or the electrically evoked twitches of detrusor muscle strips. Possible mechanisms for the discrepancy between the lack of functional effects of NS1608 per se on detrusor contractility and this drug's agonistic effect on BK(Ca) currents in isolated bladder myocytes are discussed. 3. 4-Aminopyridine (1 mM), a blocker of voltage-gated K+ (K(V)) channels, increased the tension integral 2.7-fold, on average. NS1608 (30 microM) counteracted this effect. 4. Apamin (100 nM), a selective blocker of the small conductance, Ca2+-activated K+ (SK(Ca)) channel, increased the tension integral 1.7-fold, on average. This effect was reversed by NS1608 (30 microM). 5. Ryanodine (10 microM), a modulator of the sarcoplasmic reticulum (SR) Ca2+-release channel, increased the tension integral 1.9-fold, on average. This effect was reversed by NS1608 (30 microM). 6. Iberiotoxin (IbTX, 50 nM), a selective blocker of the BK(Ca) channel, caused additional increases in the tension integral of detrusor strips pretreated with apamin or ryanodine and prevented the inhibitory effects of NS1608 (30 microM) in detrusor contractility. 7. The present study shows that blockade of repolarizing currents carried by, respectively apamin- and 4-aminopyridine-sensitive K+ channels unmasks an activation of BK(Ca) in guinea-pig urinary bladder smooth muscle strips.

The peripheral antinociceptive effect of resveratrol is associated with activation of potassium channels.

The possible participation of K(+) channels in the antinociceptive action induced by resveratrol was assessed in the 1% formalin test. Local administration of resveratrol produced a dose-dependent antinociception in the second phase of the test. The antinociception produced by resveratrol was due to a local action as its administration in the contralateral paw was not active. Local pretreatment of the injured paw with glibenclamide, tolbutamide or glipizide (ATP-sensitive K(+) channel inhibitors) did not modify resveratrol-induced antinociception. In contrast, charybdotoxin and apamin (large and small conductance Ca(2+) activated-K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) dose-dependently prevented resveratrol-induced antinociception. Local peripheral administration of glibenclamide, but not charybdotoxin or apamin, significantly reduced the antinociceptive effect produced by peripheral morphine (positive control). At the highest effective doses, none of the drugs used induced behavioral side effects as revealed by the evaluation of stepping, righting, corneal and pinna reflexes. In addition, when given alone, none of the inhibitors modified the nociceptive behavior induced by 1% formalin. The results suggest that resveratrol opens large and small conductance Ca(2+)-activated K(+) channels, but not ATP-sensitive K(+) channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K(+) channels was also suggested, but since non-selective inhibitors were used the data awaits further confirmation.