Elsevier

Cellular Signalling

Volume 19, Issue 9, September 2007, Pages 1820-1829
Cellular Signalling

Review
Protein kinase C as a stress sensor

https://doi.org/10.1016/j.cellsig.2007.05.014Get rights and content

Abstract

While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.

It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.

This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

Introduction

The protein kinase C (PKC) family of proteins is part of the larger ABC protein kinases which includes Protein Kinase A (PKA), Protein Kinase B (PKB, synonymous to Akt), and Protein Kinase C (PKC) [1], [2], [3]. All members of this superfamily have an N-terminal regulatory region and a conserved C-terminal kinase core that contains two conserved phosphorylation sites. These sites are known as the turn motif and hydrophobic motif. The regulatory regions of ABC kinases have two functions. One is to bind to the plasma membrane or other cellular targets, and the other is to inhibit the active site of the enzyme. The C-terminal region functions as the substrate binding site and phosphor-acceptor/donor site.

All ABC kinases contain an activation loop threonine that must be phosphorylated by upstream Phosphoinositide Dependent Kinase-1 (PDK-1), except protein kinase A (PKA) which is recognized by PDK-1, in vitro, but does not require PDK-1 activity in vivo. PDK-1 is constantly active, but, it's downstream substrates must be in an open conformation in order to become targets. For example, when the pleckstrin homology (PH) domain of protein kinase B (PKB) encounters Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), this opens the conformation, by disassociation of the PH domain, with the kinase core, revealing the activation loop. Once activated, PKB remains in this state. In contrast, PKCs are phosphorylated at the activation loop, but this only primes them. They still must interact with secondary messengers or other signals before becoming activated.

Section snippets

Biochemical features

There are at least 10 isoforms of PKC that are divided into 3 groups related through their primary structure [3]. In general, PKCs contain a regulatory domain, with a pseudo substrate region, as well as the elements necessary to respond to second messengers (Fig. 1). The N-terminal regulatory domain is followed by a hinge region and the kinase core which contains the substrate and ATP binding sites in the C-terminus of PKC. PKCs, once processed in the cell by priming phosphorylation events by

PKCε in the heart

PKCε has been implicated as a major factor in the phenomena of cardiac preconditioning [38]. Under hypoxic conditions PKCε translocation to Cx43 and to mitochondria and subsequent protection from ischemia are dependent upon the presence of increased mitochondrial reactive oxygen species (ROS). The requirement for PKCε was confirmed using the PKCε null mouse hearts which do not develop tolerance to antimycinA-induced ischemia [39].

Cardiac preconditioning, which has been demonstrated in many

Conclusions

Both PKCγ and PKCε have open and easily activated C1 domains which allow them to become activated by oxidative signals and ROS, without a DAG or calcium signal. These PKC isoforms play a key role in the control of both mitochondria and gap junctions during ischemic stress. This stress control appears to involve, mainly, PKCε in heart, but the additional PKCγ in neural tissues. It is not certain if both PKCs control the Cx43 gap junction protein. However, the use of the available knockout models

Acknowledgements

This review was made possible by NIH grant number P20-RR016475 (to D. Madgwick) from the INBRE Program of the National Center for Research Resources, and NIH grant number RO1-EY13421 (to D. Takemoto).

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