Differential sensitivity of expressed L-type calcium channels and muscarinic M-1 receptors to volatile anesthetics in Xenopus oocytes

Since volatile anesthetics inhibited high voltage-gated calcium channels an d G-protein-coupled M-1 muscarinic signaling, their effects upon M-1 recept or-induced modulation of L-type (alpha 1C) calcium channel was investigated . Voltage-clamped Ba2+ currents (/(Ba)) were measured in Xenopus oocytes co expressed with L-type channels and M-1 muscarinic receptors. M-1 receptor a gonist, acetyl-beta -methylcholine (MCh) inhibited the peak and late compon ents of /(Ba) in a dose-dependent manner. Analysis of /(Ba) after the treat ment with MCh or volatile anesthetics revealed that the inactivating compon ent, its time constant, and the noninactivating current were all decreased by these agents. MCh-induced inhibition followed a second messenger pathway that included G-proteins, phospholipase C, inositol-1,4,5-trisphosphate, a nd intracellular calcium [Ca2+](i). Although halothane or isoflurane inhibi ted /(Ba) their effect was not mediated through these intracellular second messengers. By using volatile anesthetics and MCh sequentially, and in vari ous combinations, the susceptibility of L-type currents and their modulatio n by M-1 receptors to volatile anesthetics were investigated. When MCh and volatile anesthetics were administered together simultaneously, a pronounce d inhibition that was approximately equal to the sum of their individual ef fects was seen. Halothane or isoflurane further inhibited the /(Ba) when ei ther volatile anesthetic was administered following the inhibition produced by prior administration of MCh. However, when MCh was administered followi ng either volatile anesthetic, its effect was significantly reduced. Thus, whereas volatile anesthetics appear to directly inhibit L-type channels, th ey also interfere with channel modulation by G-protein-coupled receptors, w hich may have functional implications for both neuronal and cardiovascular tissues.