Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 199

is predominantly located in the cytosol. Ischemia-
reperfusion events cause GSK3

In cardiomyocytes, GSK3 β

translocation from the cytosol to mitochondria.
Cardioprotection by mitochondrial ATP-sensitive K + channel before ischemia relies
on mitochondrial GSK3

β

phosphorylation (Ser9; inactivation) [ 347 ].
In ventriculomyocytes, connexin-43 phosphorylation at Ser or Tyr residues
regulates gap junction permeability, hence electrochemical coupling of cardiomy-
ocytes. Connexin-43 also localizes to the inner membrane of subsarcolemmal
mitochondria. It increases mK AT P channel activity, leading to elevated ROS pro-
duction.
Glycogen synthase kinase-3

β

operates via mitochondrial inner membrane
connexin-43 15 and mitochondrial inner membrane ATP-sensitive K + channel [ 348 ].
cardioprotection relies on opening of mK AT P channel. Activated PKC kinase and
inhibited PP2 phosphatase increase the open probability of mK AT P channels via
GSK3

β

and mitochondrial connexin-43 hemichannels, which can carry ATP.
Phosphorylation of mitochondrial connexin-43 increases its activity. Ischemic
preconditioning is supported by phosphorylation (inhibition) of glycogen synthase
kinase-3

β

β , thereby repressing mitochondrial permeability transition pore opening.

In cardiomyocytes, connexin-43, together with G β subunit of G protein,

participates in PI3K c1γ activation, hence in the cytoprotective PI3K-PKB-GSK3 β

pathway [ 349 ]. 16 In the myocardium, the PI3K-PKB-GSK3

axis enables ischemia
tolerance supported by insulin, erythropoietin, bradykinin, and adenosine receptors.
The PI3K-PKB pathway stimulates ROS production by opening of mitochondrial
ATP-sensitive K + channel that requires a certain mitochondrial concentration of
connexin-43. Endothelin-1 that acts via G-protein-coupled receptors and signals in
cooperation with connexin-43, and insulin-like growth factor-1 that targets receptor
protein Tyr kinase, without the assistance of connexin-43, cause phosphorylation
of PKB and GSK3

β

. In other words, connexin-43 is involved in cell protection
ensured by endothelin-1, but not that primed by IGF1 agent. Endothelin-1 can elicit
ROS production in mitochondria using connexin-43, but not IGF1 factor. Connexin-

β

15 Sarcolemmal and mitochondrial connexin-43 have different functions. The former is involved in
the formation of gap junctions, the latter in the production of reactive oxygen species for redox
signaling (Vol. 4 - Chap. 10. Other Major Signaling Mediators).
16 In cardiomyocytes, both class-1A and -1B PI3Ks that are coupled with different types of
receptors trigger PKB-GSK3 signaling. Receptor protein Tyr kinases and cytokine receptors

operate via class-1A PI3Ks (PI3K c1α -PI3K c1β and PI3K c1δ ), whereas G-protein-coupled receptors
activate class-1B PI3K (PI3K c1γ )usingG βγ dimer. Kinase GSK3 β is phosphorylated in response
to activation of G-protein-coupled receptors, such as δ -opioid receptor and endothelin-1 receptor,
when connexin-43 is available. On the other hand, activated IGF1 receptor does not need the
assistance of connexin-43 to cause GSK3 β phosphorylation [ 349 ]. Moreover, PKC ,ERK,
and P38MAPK are phosphorylated upon stimulation by endothelin-1, even in the absence of
connexin-43. Therefore, connexin-43 does not influence all of the signaling types initiated by G-
protein-coupled receptors [ 349 ].

β