# Impact of PKC-MAPK Signaling on Cardiac Sympathetic Overactivation in Type-2 Diabetes Mellitus

## TL;DR

This study explores how a specific signaling pathway in the sympathetic nervous system contributes to heart issues in type-2 diabetes.

## Contribution

The paper identifies the PKC-MAPK14-ADAM17 signaling pathway in satellite glial cells as a novel mechanism for cardiac sympathetic overactivation in T2DM.

## Key findings

- T2DM rats showed increased MAPK14, PKC-α, and ADAM17 expression and activity in the stellate ganglion.
- T2DM increased cardiac sympathetic nerve activity and neuronal excitability via this signaling pathway.
- Upregulated PKC-MAPK-ADAM17 signaling enhances cell excitability of cardiac postganglionic sympathetic neurons.

## Abstract

Type-2 Diabetes Mellitus (T2DM) is related to cardiac arrhythmias. The stellate ganglion (SG), part of the sympathetic nervous system, regulates heart function. Within the SG, satellite glial cells (SGCs) have gap junction channels (Cx43). Increased Cx43 permeability induces SGC depolarization and activates the PKC-MAPK14-ADAM17 signaling pathway, releasing some endogenous factors that stimulate nearby cardiac postganglionic sympathetic neurons (CPSN). This study investigated the activation of the PKC-MAPK14-ADAM17 signaling pathway in T2DM SGs and SGCs as a novel mechanism of sympathetic overactivation. A total of 56 Sprague-Dawley rats were randomly assigned to sham and T2DM groups, and T2DM was induced using a high-fat diet combined with low-dose streptozotocin. Real-time RT-PCR, Western blot, and ELISA quantified mRNA/protein expression and enzymatic activity. The patch clamp technique assessed neuronal voltage-gated Ca2+ currents and action potentials, while electrophysiological recording measured cardiac sympathetic nerve activity (CSNA). T2DM rats exhibited marked upregulation of MAPK14, PKC-α, and ADAM17 mRNA/protein in the SG, alongside elevated enzymatic activities of PKC and ADAM17. T2DM also increased Ca2+ currents and neuronal excitability in the CPSN and induced the elevation of the CSNA. Upregulated PKC-MAPK-ADAM17 signaling in the SG might contribute to cardiac sympathetic overactivation in T2DM rats by enhancing the cell excitability of the CPSN.