Protein Kinase C-ε Primes the Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel to Modulation by Isoflurane

Abstract

Background Cardioprotection by volatile anesthetic-induced preconditioning is known to involve intracellular signaling pathways. Recent studies have shown that protein kinase C (PKC) plays an important role in anesthetic-induced preconditioning. In this study, the effects of the activation of specific isozymes of PKC, specifically PKC-epsilon and -delta, on the modulation of the sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channel by isoflurane were investigated. Methods The sarcKATP current was measured in ventricular myocytes isolated from guinea pig hearts using the whole cell configuration of the patch clamp technique. Peptides that induced the translocation of specific PKC isozymes were used to activate PKC-epsilon and PKC-delta. Results Under whole cell conditions, isoflurane alone was unable to elicit the opening of the sarcKATP channel. Pretreatment with the specific PKC-epsilon activator, PP106, primed the sarcKATP channel to open in the presence of isoflurane. The resulting sarcKATP current densities in the presence of 0.88 mm isoflurane were 6.5 +/- 6.0 pA/pF (n = 7) and 40.4 +/- 18.2 pA/pF (n = 7) after pretreatment with 100 and 200 nm PP106, respectively. The PKC-epsilon antagonist PP93 abolished this effect. A scrambled peptide of the PKC-epsilon activator PP105 did not prime the sarcKATP channel. The PKC-delta activator PP114 was significantly less effective in priming the sarcKATP channel. 5-Hydroxydecanoate significantly attenuated the effect of the PKC-epdsilon activator on the sarcKATP channel. In addition, immunohistochemical analysis showed that the PKC-epsilon isoform translocated to both the mitochondria and sarcolemma after anesthetic-induced preconditioning, whereas the PKC-delta isoform translocated to the mitochondria. Conclusion The PKC-epsilon isozyme primed the sarcKATP channel to open in the presence of isoflurane. The PKC-delta isozyme was significantly less effective in modulating the isoflurane effect on this channel.

KATPChannels in the Cardiovascular System

“…B: the ATP-binding cassette transporter family consists of 7 subfamilies (ABCA to ABCG) with 48 subfamily members (169). The membrane topology of the "half transporters" (such as the ABCG family) has an NH 2 -terminal nucleotide binding fold (NBF), 6 TMs, and an intracellular COOH terminus. "Full transporters" (such as ABCC7 or CFTR) appear as a tandem repeat of the 6 TM domains, with 2 NBFs.…”

“…activates cardiac K ATP channels directly (6,364,365,384,501,823,937) and upregulates K ATP channel surface density (199,824). Moreover, the Ca 2ϩ -dependent and Ca 2ϩ -independent PKCs may act synergistically to activate K ATP channels (36, 384).…”

Protein kinase Cϵ interacts with cytochrome c oxidase subunit IV and enhances cytochrome c oxidase activity in neonatal cardiac myocyte preconditioning

“…Previous Western-blot studies, however, have indicated that little PKCε exists inside mitochondria in the basal state, suggesting that PKCε must translocate to mitochondria following PC in order to interact with COIV. Following activation, PKCε has been reported to exist inside mitochondria isolated from mouse hearts [33], NCMs [51] and guinea-pig cardiac myocytes [52]. For example, Baines et al [19] found that PKCε forms intramitochondrial signalling complexes with MAPK following PC of mouse myocardium.…”

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

“…Indeed, the mechanisms underlying isoflurane-induced tolerance are not completely known, but studies of myocardial ischemia have shown that isoflurane-induced tolerance shared several cellular mechanisms with ischemic tolerance including opening of adenosine triphosphate-sensitive potassium channels (K ATP channels), an adenosine receptor-mediated pathway, and a protein kinase C (PKC)-mediated pathway. 7,8 Involvement of adenosine A 1 receptors and K ATP channels in the development of cerebral ischemic tolerance induced by sublethal ischemia has been well studied. In our previous study, we found that glibenclamide, an adenosine triphosphate-regulated potassium channel blocker, abolished the tolerance to focal cerebral ischemia induced by repeated isoflurane anesthesia.…”