Page 13 - CBAC Newsletter 2016
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with beta adrenergic receptors or may keep step with a 6. L-735821 (L-7)
signal cascade of the beta-adrenergic receptors. These
effects may happen at the threshold concentrations of L-735821 is an analog to cholecystokinin-B antagonists
drug (100µM), leading to potentiation odfruthg,einIKhs icbuitriroennt. (specific antagonists that block the receptor sites for the
With increasing concentrations of the peptide hormone cholecystokinin) (Fig.3) (203). L-7 is a
becomes dominant, possibly through the direct potent blocker of both oKcCcNyQte1s.anLd-7Ikiss channels
interactions between the drug and the KCNQ1 channel expressed in Xenopus slightly more
(193). The potentiation and inhibition of azimilide on IKs I2pto0st0aecnnttMioonnonpIkrsIoktslhoaannngdsKKtChCNeNQdQ1u1rc,ahrteaiosnnpneeoclfsttivh(IeeCly5c0)a=(rTda4iab0clenaM2c)tai(o2nn1d0).
channels seem to be underlined by independent
mechanism, however, inhibition is the main component,
with an overall reduction of steady state currents (193). potential (210). L-7 has no effect on KCNQ2 channels
at 10 µM concentration (203,210). The effect of L-7 is
5. L-768673 voltage-independent (210).
The benzodiazepine analog L-768,673 (Fig. 3) is very L-735821 physically blocks the channel pore by binding
r(pICIeCoast5cpe0hen=actnt6oinvnneeMlIlskys))(cI((hC2Ta5a00nb3=nl)e.e6l2Csµ)o,ManwtvahneneMrdrseec1aloyµsn,MciLt-e7ions6ntl8reIak6srt7siao3npndoshtaIeCsanntchooanenfInkfreeoclsrt, to T312 of the pore helix, and I337, F339, F340, and
A344 of the S6 transmembrane segment (210).
ownithItovoarriIok1ucshtaensnteedlsc.hTahnenreelfsorreev, ethaeleedffitesctsseloefcLt-i7vi6ty8,673 7. Clofilium
Clofilium is an antagonist on KCNQ1 channels (Fig.3),
Lfo-7r6IK8s,c6h7a3nncaenls (204). These results suggested that wbliothckasnmICu5r0inleesKsCtNhaQn21c0haµnMne(Tlsabalte220) (211). It partially
be a potential anti-arrhythmic therapeutic µM when the
(158). This ligand was first reported to have no effect current is elicited by depolarized voltage from -80 to
on the function or structure of rat cochlea after oral +40 mV (77). At 10 µM concentration, clofilium inhibits
administration (205); however, another study reported KCNQ3 currents by 30% (202). It inhibits KCNQ5
an ototoxic side effect for L-768,673 after intravenous currents by 40% at 30 µM concentration (77).
administration, predicting ototoxicity because of its
esafffeec, twoitnhIKosnclyhasnlignhetlse(f2fe0c6t)s. Generally, L-768,673 is (cCIuClor5rf0ieli=nutm5s0,irsµeamspbealocnctdikvIeeCrly5o0) f(=Tca1abrµdleMia2co) In(K2sI1Kas1na,d2n1IdK2rIc)K.rucrhreanntnsel
on the studied animals with
only moderate QT prolongation (204). L-768673 induces
heterotaxia, predicting a functional role for KCNQ1 chan-
nels in early embryonic asymmetry (207). L-678,673 cCinulhorirfbieliinutstmaKtdC3oNe0Qs1µnMcoh,taiitnnihnnihebilibst.iItkWss chahislaemnitnueicnlhshiaabssit8se0f2f-e59c%0ti%voefolIyfKSas it
effects have been reported with granulosa cells (which KCNQ1 current at the same concentration (212,213).
have many roles, such as ovulation, implantation, and
fertilization), suggesting that Iks channels are involved in
these cells (208,209).
Conclusions
The relaxant effect produced by the benzodiazepine
R-L3 (Fig.2) on pieces of preconstricted mesenteric The KCNQ voltage-gated potassium channels are
arteries was completely reversed by L-768,673 at 10µM involved in many physiology and pathophysiology
concentration. No effect was noticed on endothelium functions. The KCNQ1 protein plays roles in the
removal (158). The less potent relaxant effect of functioning of the heart, inner ear, and intestines.
mefenamic acid was only partially reversed by KCNQ2/3, and to some extent KCNQ5, are involved in
L-768,673, which may be due to the inhibitory effect of M-current, and are distributed in neurons. KCNQ4 plays
mefenamic acid on Ca2+-activated Cl- channels (165). key roles in the vestibular and auditory sytems. The
While L-768,673 has no effect on KCNQ5 currents, it has KCNQ5 subunit may be involved in roles in skeletal
shown a remarkable inhibitory effect on KCNQ4 currents muscles, however, this still needs to be confirmed.
produced at potentials from positive to 0 mV, an action Modulating of KCNQ channels may help to manage many
that has not been noticed with other blockers (158). hyperexcitability disorders, for instance epilepsy, pain
These functional studies of L-768,673 may show that related disorders and cardiac arrhythmias (98,214).
the KCNQ4 subunit is involved in many activities (158).
Compounds either enhancing or inhibiting KCNQ chan-
nels have been used clinically to treat various diseases.
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