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Non-Ser36 phosphorylated p66Shc inhibits TRPC-dependent and TRPC-independent calcium influx in vascular smooth muscle

Perrin Schupbach1, Bradley Miller1, Andrey Sorokin1

  • 1Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.

Biochemical and Biophysical Research Communications
|October 14, 2025
PubMed

Insights

Increased adaptor protein p66Shc expression impairs vascular responses in hypertension by altering calcium influx in renal smooth muscle cells. This suggests new therapeutic targets for kidney disease.

Area of Science:

  • Cardiovascular Biology
  • Renal Physiology
  • Molecular Medicine

Background:

  • Hypertension is a major cause of chronic kidney disease and kidney failure.
  • Increased p66Shc expression is linked to vascular dysfunction and renal damage in hypertensive rats.
  • Reduced renal microvessel contractility involves inhibited calcium influx via TRPC channels in smooth muscle cells.

Purpose of the Study:

  • To investigate the mechanism by which p66Shc regulates calcium influx in rat renal smooth muscle cells.
  • To determine the role of p66Shc phosphorylation and TRPC channel activity in hypertension-induced renal damage.

Main Methods:

  • Analysis of TRPC expression profiles in renal smooth muscle cells from Dahl-SS and mutant rats.
  • Confocal imaging with Fluo4-AM to measure calcium influx.
  • Utilized TRPC inhibitors and specific activators to assess channel function and p66Shc interaction.

Main Results:

  • Endothelin-mediated calcium influx is primarily mediated by TRPC6 channels.
  • p66Shc suppresses TRPC6 activation by Oleoyl-acetyl-sn-glycerol, independent of Ser36 phosphorylation.
  • p66Shc inhibits calcium entry independently of TRPCs in response to ATP, indicating broad calcium dynamics control.

Conclusions:

  • p66Shc regulates calcium entry in renal smooth muscle cells through mechanisms independent of Ser36 phosphorylation.
  • These findings elucidate p66Shc's role in impaired vascular responses and offer insights into hypertension-related kidney disease.

Keywords:
CalciumP66ShcTransient receptor potential canonical channels

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