Faculty Collaboration Database

Non-Ser36 phosphorylated p66Shc inhibits TRPC-dependent and TRPC-independent calcium influx in vascular smooth muscle cells. Biochem Biophys Res Commun 2025 Nov 01;787:152776

Date

10/15/2025

Pubmed ID

41086682

Pubmed Central ID

PMC12574702

DOI

10.1016/j.bbrc.2025.152776

Scopus ID

2-s2.0-105018336521 (requires institutional sign-in at Scopus site)

Abstract

Hypertension is a highly prevalent condition that causes chronic kidney disease and eventually kidney failure. Increased expression of adaptor protein p66Shc has been associated with attenuated vascular responses to stimuli and renal damage in hypertensive Dahl salt-sensitive (SS) rats. Reduced contractility of renal microvessels was linked to inhibition of calcium influx through transient receptor canonical (TRPC) channels in vascular smooth muscle cells (SMCs). Prevention of Ser36 phosphorylation of p66Shc, which stimulates mitochondrial translocation, exaggerated modulation of TRPC activity. While TRPC inhibition was dependent on p66Shc expression, the underlying mechanism is unresolved. The expression profiles of TRPCs in rat renal SMCs from Dahl-SS and mutant rats were determined. Confocal imaging with Fluo4-AM was used to assess calcium entry in response to various stimuli, and TRPC inhibitors were used to evaluate relative contributions of different channels. Endothelin-mediated calcium influx was primarily driven by TRPC6. Direct activation of TRPC6 by Oleoyl-acetyl-sn-glycerol was possible in SMCs expressing wild-type p66Shc but was greatly suppressed in cells expressing S36A mutant p66Shc, suggesting TRPC inhibition by p66Shc is independent of Ser36 phosphorylation. P66Shc inhibited calcium entry independent of TRPCs in response to ATP, indicating broad control of calcium dynamics by p66Shc. Overall, these results provide insight into p66Shc regulation of calcium entry that contributes to impaired vascular responses in hypertension.

Author List

Schupbach P, Miller B, Sorokin A

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cells, Cultured
Hypertension
Male
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Phosphorylation
Rats
Rats, Inbred Dahl
Serine
Src Homology 2 Domain-Containing, Transforming Protein 1
TRPC Cation Channels
TRPC6 Cation Channel