K+ channel activators

Delayed-rectifier K+ channels activate with a delay and mediate outwardly-rectifying K+ currents. These channels may make a significant contribution to the icpolarizing phase of nervous action potentials. 

Kd 50 nM for GIRK [G-protein-activated inwardly rectifying K+ channel] activation) and persistent in the absence of competing Ga-GDP, Py-effector binding is not irreversible. 

Kelly MJ, Ronnekleiv OK, Ibrahim N, Lagrange ATI, Wagner EJ (2002) Estrogen modulation of K+ channel activity in the hypothalamic neurons involved in the control of the reproductive axis. Steroids 67 447-456... 

Isenberg In cell-free patches the SR is adjacent to the surface membrane. Does K+ channel activity vary quite a lot from patch to patch ... 

Hwang J-U, Suh SS, Yi H, Kim J, Lee Y. Actin filaments modulate both stomatal opening and inward K+ channel activities in guard cells of Vidafaba. Plant Physiol 1997 115 335-342. 

Kelley WP, Wolters AM, Sacks JT, Jockusch RA, Jurchen JC, Williams ER, Sweedler JV, Gilly WF (2003) Characterization of a Novel Gastropod Toxin (6-Bromo-2-mercaptotrypt-amine) That Inhibits Shaker K Channel Activity. J Biol Chem 278 34934... 

Gilani AH, Khan AU, Ghayur MN, Ali SF, Herzig JW. 2006. Antispasmodic effects of Rooibos tea (Aspalathus linearis) is mediated predominantly through K + -channel activation. Basic Clin Pharmacol Toxicol 99 365-373. 

Subsequent activation of the kinases, protein kinase C (PKC) and protein kinase A (PKA) and consequent protein phosphorylation can enhance Ca2+ channel function, opposing G0-mediated inhibition, or can modify K+ channel activity, so indirectly altering action potential-induced Ca2+-entry. 

Flupirtine was the first compound identified to affect KCNQ channels and has been used in man to treat pain. However, only recently has this drug been shown to be an activator of Kv7 channels (see Munro and Dalby-Brown 2007). The clinical efficacy of flupirtine was originally postulated to occur through receptor-dependent mechanisms, but as noted by Munro and Dalby-Brown (2007) it is likely that Kv7 channel activation occurs at clinically relevant exposure levels. Retigabine, a flupirtine analog, is currently in clinical trials for the treatment of epilepsy and pain and has been the most widely used tool to explore both the in vitro and in vivo effects of Kv7 activation. This compound was initially shown to increase K+ channel activity in a neuroblastoma cell line (Rundfeldt 1997 see also Rundfeldt 1999) and subsequently was... 

On the other hand, K+ channel activators such as valinomycin (Rouzaire-Dubois et al. 1993) and minoxidil (Abdul et al. 2003) do the opposite promoting tumor cell proliferation. 

If K+ channels are inhibited, cancer cell proliferation is impaired, whereas if K+ channel activities are enhanced, cancer cell growth is promoted. One exception is quercetin it has been reported to block Kv channels (Rouzaire-Dubois et al. 1993) and to activate BKca as well (Cogolludo et al. 2007 Kuhlmann et al. 2005). Pharmacological tools opened the way toward the understanding of the role of K+ channels in cell proliferation... 

Note that this is not an exhaustive collection of all related studies and the purpose of this table is merely to indicate the types of K+ channels involved in cancer cell growth and the types of chemical structures that are able to alter the growth of various types of cancer cells by changing K+ channel activities)... 

Fig. 4 Schematic illustration of the potential target sites to reduce K+ channel activity leading to decreases in tumor cell proliferation, if indicate reduction dashed arrows indicate negative regulation...

Roderick C, Reinach PS, Wang L, Lu L (2003) Modulation of rabbit corneal epithelial cell proliferation by growth factor-regulated K+ channel activity. J Membr Biol 196 41-50... 

Xu B, Wilson BA, Lu L (1996) Induction of human myeloblastic ML-1 cell G1 arrest by suppression of K+ channel activity. Am J Physiol Cell Physiol 40 C2037-C2044... 

Xu DZ, Wang L, Dai W, Lu L (1999) A requirement for K+-channel activity in growth factor-mediated extracellular signal-regulated kinase activation in human myeloblastic leukemia ML-1 cells. Blood 94 139-145... 

Direct coupling of a G protein to the heart K+ channel activated by muscarinic ligands was demonstrated in a cell-free system using inside-out patches. Addition to the bath (the cytoplasmic face of the patch) of GTPyS leads, after a lag, to permanent activation of K+ channels [144]. Similarly, addition of purified PTX-sensi-tive G protein from human erythrocytes (referred to originally as Gj ) or its a subunit complexed with GTPy and free of /3y subunits, also stimulates these channels, provided the G protein is preactivated by GTPyS [145]. These results defined the existence of a Gk and identified it physically as an ajSy heterotrimer and a PTX substrate. 

Fig. 13. Characteristics of activation of a G protein-gated K+ channel as seen in endocrine (GH3) cells. Panel a, activation of the channel by 100 /u,M GTP-yS panel b, activation of the K+ channel by 2 nM GTP-activated Gk (Gk ) panel c, dependence of K+ channel activation by receptors (10 /u.M acetylcholine, ACh) on GTP (when present 100 /xM) panel d, sensitivity of GH, cell Gk to uncoupling by PTX, lack of effect of 2 nM GTP S-activated Gs (Gs ) and reconstitution of receptor (somatostatin, SST)-K channel coupling by exogenously added native Gk (2 nM) in the presence of 100 juM GTP (W, wash) panel e, effect of ak , i.c., ak-GTPyS resolved from fiy dimers, added at 0.5, 5 and 25 pM panel f, lack of effect of fiy dimers on K+ conductance of an ak responsive membrane. For rest of conditions see legend to Fig. 4 and Refs. 144, 145 and 232.

Freedman JE, Weight FF (1988) Single K+ channels activated by D2 dopamine receptors in acutely dissociated neurons from rat corpus striatum. Proc Natl Acad Sci USA 35 3618-3622. 

Freedman JE, Weight FF (1989) Quinine potently blocks single K+ channels activated by dopamine D-2 receptors in rat corpus striatum neurons. Eur J Pharmacol 164 341-346. 

Perozo, E., Cortes, D. M., and Cuello, L. G. (1999). Structural rearrangements underlying K+-channel activation gating. Science 285, 73-78. 

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