Sodium current modulation by a tubulin/GTP coupled process in rat neonatal cardiac myocytes.
Microtubule disassembly by colchicine increases spontaneous beating of neonatal cardiac myocytes by an unknown mechanism. Here, we measure drug effects on spontaneous calcium transients and whole cell ionic currents to define the route between microtubule depolymerization and the increase in the rate of contraction. Colchicine treatment disassembles microtubules resulting in free tubulin dimers, thereby increasing the spontaneous beating frequency and changing both the rates of rise and decay of calcium transients. In addition, colchicine treatment produces an increase of the sodium current (I(Na)) while I(Ca) is not modified. The colchicine-enhanced I(Na) was blocked by the addition of 10 microM TTX. In addition, the colchicine-induced increase of I(Na) was prevented when GTP was omitted from the patch pipette. Vinblastine also depolymerizes microtubules but re-aggregates tubulin into paracrystalline structures. Free tubulin dimers are not increased with vinblastine treatment. We found no modification in calcium transients or I(Na) in the presence of vinblastine. Action potential durations measured at 50 % and 90 % repolarization were shorter, and the dV/dt was larger, in colchicine-treated cells compared to untreated cells. The resting membrane potential and overshoot of the action potentials were comparable in both kinds of cells. Our data suggest that release of free tubulin dimers may activate G proteins, which in turn modulate the sodium channel. An increase in whole cell I(Na) changes the spontaneous firing rate and this may be the underlying cause of the increase in the frequency of contraction in neonatal cardiac myocytes. We suggest a new role for dimeric tubulin in regulating membrane excitability.
Motlagh
Delara
D
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Alden
Kris J
KJ
Russell
Brenda
B
García
Jesús
J
D000818:Animals; D000831:Animals, Newborn; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D019281:Dimerization; D006160:Guanosine Triphosphate / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology*; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D014747:Vinblastine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D011108:Polymers; D014404:Tubulin; D014747:Vinblastine; D006160:Guanosine Triphosphate; D012964:Sodium; D003078:Colchicine