Effects of Serine/Threonine Protein Phosphatases on Ion Channels in Excitable Membranes

Abstract

This review deals with the influence of serine/threonine-specific protein phosphatases on the function of ion channels in the plasma membrane of excitable tissues. Particular focus is given to developments of the past decade. Most of the electrophysiological experiments have been performed with protein phosphatase inhibitors. Therefore, a synopsis is required incorporating issues from biochemistry, pharmacology, and electrophysiology. First, we summarize the structural and biochemical properties of protein phosphatase (types 1, 2A, 2B, 2C, and 3-7) catalytic subunits and their regulatory subunits. Then the available pharmacological tools (protein inhibitors, nonprotein inhibitors, and activators) are introduced. The use of these inhibitors is discussed based on their biochemical selectivity and a number of methodological caveats. The next section reviews the effects of these tools on various classes of ion channels (i.e., voltage-gated Ca(2+) and Na(+) channels, various K(+) channels, ligand-gated channels, and anion channels). We delineate in which cases a direct interaction between a protein phosphatase and a given channel has been proven and where a more complex regulation is likely involved. Finally, we present ideas for future research and possible pathophysiological implications.

Regulation of Metabotropic Glutamate Receptor 7 (mGluR7) Internalization and Surface Expression by Ser/Thr Protein Phosphatase 1

“…1, A-C). Okadaic acid is a potent inhibitor of both PP1 and PP2A, but 100-fold more potent for PP2A than for PP1 (IC 50 value is 10 -270 and 0.2-2 nM for PP1 and PP2A, respectively) (11,18,19). Therefore, the inability of low dose okadaic acid to enhance mGluR7 phosphorylation suggests that Ser-862 of mGluR7 is a target of PP1 rather than PP2A.…”

“…Similar to protein kinases, protein phosphatases actively participate in regulating synaptic changes and the activity-dependent alterations of synaptic transmission (11,12). It is clear that PKC dramatically regulates mGluR7 trafficking, but the phosphatase(s) that target mGluR7 remain unknown.…”

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

“…Kinases play important, well documented, roles in the regulation of numerous cellular functions [10,43,67]. The physiological significance of serine/threonine protein phosphatases has also been appreciated, and these enzymes have been implicated in the regulation of ion channels, synaptic plasticity, exocytosis, and apoptosis [31,36,58,70].…”

T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4

“…Lastly, when 2 luciferase reporter assays were employed to test whether PP4 regulates IL-2 transcriptions, we found that the inhibition of PP2A/PP4/PP6 by OA failed to reduce the activity of IL-2 promoter (Fig. 4D) even at a relatively high dose of 50 nM, 25 hinting that PP4 deficient may not significantly alter IL-2 transcription. Combined with the mixed proliferation data (Fig.…”

“…3 Treatment with OA (and the resulting suppression of PP2A, PP4 and PP6) has been reported to down-regulate the mRNA level of IL-2 25 through multiple pathways. 27,31 In addition, our data showed that activated PP4-deficient T cells produced significantly less IL-2 (p D 0.007) (as well as IL-4 and IL-10) ( Fig.…”