Related Experiment Video

Updated: Aug 14, 2026

Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting
10:08

Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

Published on: December 9, 2022

Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation

Louis S Premkumar1, Manish Raisinghani, Sandeep C Pingle

  • 1Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA. lpremkumar@siumed.edu

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|December 13, 2005
PubMed

Insights

Protein kinase C (PKC) activation downregulates the cold-sensing TRPM8 channel but upregulates the heat-sensing TRPV1 channel. This imbalance may worsen inflammatory pain by reducing soothing cool sensations.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Sensory Physiology

Background:

  • Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are key ion channels involved in thermosensation.
  • These channels are crucial for transmitting sensory information from peripheral nerve terminals to the central nervous system.
  • They also play a significant role in synaptic transmission within the dorsal root ganglion (DRG) and dorsal horn (DH) neuronal circuit.

Purpose of the Study:

  • To investigate the differential regulation of TRPM8 and TRPV1 by protein kinase C (PKC).
  • To elucidate the role of TRPM8 and TRPV1 in synaptic transmission at the DRG-DH synapse.
  • To understand the implications of TRPM8 and TRPV1 regulation in inflammatory thermal hyperalgesia.

Main Methods:

  • Utilized cloned and native receptors to study TRPM8 and TRPV1 function.
  • Investigated the effects of bradykinin on TRPM8 activity in DRG neurons.
  • Measured spontaneous and miniature excitatory postsynaptic currents (EPSCs) to assess synaptic transmission.
  • Examined the role of PKC-mediated dephosphorylation in TRPM8 regulation.

Main Results:

  • PKC activation functionally downregulates TRPM8, inhibiting membrane currents and increasing intracellular Ca2+.
  • Conversely, PKC activation upregulates TRPV1 activity.
  • PKC activation blunts TRPM8-mediated synaptic transmission while facilitating TRPV1-mediated transmission.
  • TRPM8 downregulation is linked to PKC-mediated dephosphorylation, reversible by phosphatase inhibitors.

Conclusions:

  • PKC differentially regulates TRPM8 and TRPV1, leading to opposing effects on synaptic transmission.
  • The downregulation of TRPM8 by PKC may exacerbate inflammatory thermal hyperalgesia by diminishing the counteracting cool sensation.
  • Understanding these regulatory mechanisms offers potential therapeutic targets for pain management.

More Related Videos

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins11:25

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins

Published on: October 4, 2017

A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice08:35

A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice

Published on: March 17, 2015

Related Concept Videos

Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...