Stimulation of TRPV1 channels activates the AP-1 transcription factor

Abstract

Transient receptor potential vanilloid 1 (TRPV1) channels were originally described as the receptors of capsaicin, the main constituent of hot chili pepper. The biological functions of TRPV1 channels include pain sensation and inflammatory thermal hyperalgesia. Here, we show that stimulation of HEK293 cells expressing TRPV1 channels (H2C1 cells) with capsaicin or the TRPV1 ligand resiniferatoxin activated transcription mediated by the transcription factor AP-1. No cell death was occurring under these experimental conditions. The AP-1 activity was not altered in capsaicin or resiniferatoxin-stimulated HEK293 cells lacking TRPV1. We identified the AP-1 DNA binding site as the capsaicin/resiniferatoxin-responsive element. Stimulation with the TRPV1 ligand N-arachidonoyldopamine increased AP-1 activity in a TRPV1-dependent and TRPV1-independent manner. Stimulation of TRPV1 channels induced an influx of Ca²⁺ into the cells and this rise in intracellular Ca²⁺ was essential for activating AP-1 in capsaicin or resiniferatoxin-stimulated cells. N-arachidonoyldopamine stimulation induced a rise in intracellular Ca²⁺ in a TRPV-1 dependent and independent manner. AP-1 is a dimeric transcription factor, composed of proteins of the c-Jun, c-Fos and ATF families. Stimulation of TRPV1 channels with capsaicin increased c-Jun and c-Fos biosynthesis in H2C1 cells. The signal transduction of capsaicin, leading to enhanced AP-1-mediated transcription, required extracellular signal-regulated protein kinase ERK1/2 as a signal transducer and the activation of the transcription factors c-Jun and ternary complex factor. Together, these data suggest that the intracellular functions of TRPV1 stimulation may rely on the activation of a stimulus-regulated protein kinase and stimulus-responsive transcription factors.

Keywords: Calcium; Capsaicin; Capsaicin, PubChem CID: 24896598; ERK; N-arachidonoyldopamine, PubChem CID: 5282105; PD98059, PubChem CID: 4713; Resiniferatoxin, PubChem CID: 5702546; TRPV1; c-Fos; c-Jun.