PKC regulation of ion channels: The involvement of PIP2

Figure 1. Schematic representation of PKC isozyme structures and conventional PKC (cPKC) activation. A, C1 (orange) domains in the N-terminal region bind diacylglycerol (DAG) and phorbol esters like phorbol myristate acetate (PMA). The C2 domain (blue) binds anionic lipids and calcium. The pseudosubstrate region (blue), which is located on the N-terminal end of the C1 domain, is a sequence of amino acids that mimics a substrate; the C1 domain in aPKCs binds PIP3 or ceramide. The C-terminal catalytic domain contains the ATP-binding domain C3 (magenta) and the substrate binding domain C4 (magenta). B, hydrolysis of PIP2 by phospholipase C releases two second messengers, DAG and inositol triphosphate (IP3). IP3 releases calcium from the endoplasmic reticulum (ER), which binds to the C2 domain of cPKCs while DAG binds to the C1 domain; the pseudosubstrate is released resulting in activation of cPKC and translocation to the cell membrane. (Purple circles, Ca2+; green, IP3 receptor in ER). aPKC, atypical PKC; PIP2, phosphatidylinositol (4,5) bisphosphate.

Figure 2. PIP2is a master regulator of the function of ion channels (22, 23, 24, 27, 86, 103, 112, 171, 172). Ten different ion transporting membrane protein families are shown to be dependent on PIP2 for their activity and the specific direction of the control of the activity of these proteins by PIP2 is indicated. PIP2, phosphatidylinositol (4,5) bisphosphate.

Figure 3. PKC can regulate the activity of ion channels in a PIP2-dependent manner (31, 39, 57, 58, 63, 95, 173). Examples of ion channels where PKC regulation of their activity has been linked to alteration of channel–PIP2 interactions. PIP2, phosphatidylinositol (4,5) bisphosphate.

Figure 4. D228 and phosphorylated S196 compete for R201 to gate the GIRK2 channel (55). In the absence of Na+ and phosphorylation of S196, the D228 residue (that can bind Na+) forms a salt bridge interaction with R201 stabilizing the helix bundle crossing (HBC) gate of the GIRK2 channel in the constricted conformation (top). Phosphorylation of S196 competes away R201 from D228 causing HBC channel gate dilation (bottom). GIRK, G-protein-gated inwardly rectifying K+ channel.