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Diabetic neuropathy: inhibitory G protein dysfunction involves PKC-dependent phosphorylation of Goalpha

Yu Shangguan1, Karen E Hall, Richard R Neubig

  • 1Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.

Journal of Neurochemistry
|July 31, 2003
PubMed

Insights

Diabetic neuropathy impairs inhibitory G protein function in dorsal root ganglia (DRGs) due to increased protein kinase C (PKC)-dependent phosphorylation of Goalpha. This suggests an isoform-specific PKC pathway contributes to nerve dysfunction in diabetes.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Diabetology

Background:

  • Diabetic neuropathy is a common complication of diabetes.
  • Impaired inhibitory G protein signaling is implicated in neuropathic pain.
  • The role of protein kinase C (PKC) in diabetic neuropathy is not fully understood.

Purpose of the Study:

  • To investigate the hypothesis that decreased inhibitory G protein function in diabetic neuropathy is linked to increased PKC-dependent phosphorylation of the Goalpha subunit.
  • To explore the specific PKC isoforms involved in this process.

Main Methods:

  • Utilized streptozotocin-induced diabetic rat model.
  • Assessed opioid-mediated inhibition of cyclic AMP in dorsal root ganglia (DRGs).
  • Measured basal and PKC-activated phosphorylation of Goalpha using 32Pi labeling and phospho-specific antibodies.
  • Analyzed the phosphorylation status of different PKC isoforms (alpha, betaII, delta).

Main Results:

  • Diabetic rats showed significantly reduced opioid-mediated inhibition of cyclic AMP in DRGs compared to controls.
  • DRGs from diabetic rats exhibited increased basal and PKC-activated phosphorylation of Goalpha, indicating heightened endogenous phosphorylation.
  • PKC activation failed to further increase Goalpha phosphorylation in diabetic DRGs, unlike in controls.
  • Specific changes in PKC isoform phosphorylation were observed: PKC-alpha increased, PKC-betaII remained unchanged, and PKC-delta decreased in diabetic DRGs.

Conclusions:

  • Diminished inhibitory G protein function in diabetic neuropathy involves an isoform-specific PKC-dependent pathway.
  • Increased PKC-dependent phosphorylation of Goalpha is a key mechanism contributing to impaired G protein signaling in diabetic DRGs.
  • These findings highlight a potential therapeutic target for managing diabetic neuropathy.

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