EFFECT OF SPECIFIC ION-CHANNEL BLOCKERS ON CULTURED SCHWANN-CELL PROLIFERATION

Mitogenesis in a variety of tissues is known to be inhibited by K+ cha nnel blockers such as tetraethylammonium (TEA) and 4-aminopyridine (4- AP). Using radiolabeled thymidine as a proliferation index we have exa mined what role, if any, specific K+ channels have in cultured Schwann cells that have been induced to proliferate by pre-exposure to mitoge ns. TEA and 4-AP are 'broad-spectrum'' in that they block a variety of different types of K+ channel. In contrast, we found that alpha-dendr otoxin (alpha-DTX), a specific blocker of the type 1 fast delayed rect ifier current (the largest component of Schwann cell K+ current) does not affect proliferation, suggesting that type 1 current may not be in volved in mitogenesis. This suggestion is supported by our finding tha t the values of the K-D for the mitogenic effect (722 nM, 4-AP; 13 mM, TEA) are much larger than the corresponding electrophysiological valu es for type 1 channels (0.1 mM, 4-AP; 0.2 mM, TEA). Charybdotoxin (200 nM) and iberiotoxin (100 nM), inhibitors of Ca2+-activated K+ channel s, cesium (5 mM), an inhibitor of inward rectifier channels, and furos emide (100 mu M), which blocks Na+/K+/Cl- cotransport, all had no effe ct on proliferation. Interestingly, 4,4'-diisothiocyanatostilbene 2,2' -disulphonate (DIDS), which blocks voltage-gated Cl- channels, reduced proliferation. In summary, broad-spectrum K+ channel blockers inhibit Schwann cell proliferation, but inhibitors specific for type 1, Ca2+- activated, and inward rectifier K+ channels do not. Whether the inhibi tion is mediated by type 2 K+ channels, by an as yet unidentified Schw ann cell K+ channel, or by another mechanism remains unclear. (C) 1998 Wiley-Liss, Inc.