RT Journal Article
SR Electronic
T1 Mechanisms of inhibition of T-type calcium current in the reticular thalamic neurons by 1-octanol: implication of the protein kinase C pathway
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.059931
DO 10.1124/mol.109.059931
A1 Pavle M Joksovic
A1 WonJoo Choe
A1 Michael T Nelson
A1 Peihan Orestes
A1 Barbara C Brimelow
A1 Slobodan M Todorovic
YR 2009
UL http://molpharm.aspetjournals.org/content/early/2009/10/21/mol.109.059931.abstract
AB Recent studies indicate that T-type calcium channels (T-channels) in the thalamus are cellular targets for general anesthetics. Here, we recorded T-currents and underlying low-threshold calcium spikes from neurons of nucleus reticularis thalami (nRT) in brain slices from young rats and investigated the mechanisms of their modulation by an anesthetic alcohol, 1-octanol. We found that 1-octanol inhibited native T-currents at subanesthetic concentrations with an IC50 of about 4 μM. In contrast, 1-octanol was up to 30-fold less potent in inhibiting recombinant CaV3.3 T-channels heterologously expressed in human embryonic kidney (HEK) cells. Inhibition of both native and recombinant T-currents was accompanied by a hyperpolarizing shift in steady-state inactivation indicating that 1-octanol stabilized inactive states of the channel. To explore the mechanisms underlying higher 1-octanol potency in inhibiting native nRT T-currents, we tested the effect of protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA) and PKC inhibitors. We found that PMA caused a modest increase of T-current while the inactive PMA analog, 4α-PMA failed to affect T-current in nRT neurons. In contrast, Go 6976, an inhibitor of calcium-dependent PKC, decreased baseline T-current amplitude in nRT cells and abolished the effects of subsequently applied 1-octanol. The effects of 1-octanol were also abolished by chelation of intracellular calcium ions with BAPTA. Taken together, these results suggest that inhibition of calcium-dependent PKC signaling is a possible molecular substrate for modulation of T-channels in nRT neurons by 1-octanol.The American Society for Pharmacology and Experimental Therapeutics