β-Arrestin 2 and ERK1/2 Are Important Mediators Engaged in Close Cooperation between TRPV1 and µ-Opioid Receptors in the Plasma Membrane

Abstract

The interactions between TRPV1 and µ-opioid receptors (MOR) have recently attracted much attention because these two receptors play important roles in pain pathways and can apparently modulate each other’s functioning. However, the knowledge about signaling interactions and crosstalk between these two receptors is still limited. In this study, we investigated the mutual interactions between MOR and TRPV1 shortly after their activation in HEK293 cells expressing these two receptors. After activation of one receptor we observed significant changes in the other receptor’s lateral mobility and vice versa. However, the changes in receptor movement within the plasma membrane were not connected with activation of the other receptor. We also observed that plasma membrane β-arrestin 2 levels were altered after treatment with agonists of both these receptors. Knockdown of β-arrestin 2 blocked all changes in the lateral mobility of both receptors. Furthermore, we found that β-arrestin 2 can play an important role in modulating the effectiveness of ERK1/2 phosphorylation after activation of MOR in the presence of TRPV1. These data suggest that β-arrestin 2 and ERK1/2 are important mediators between these two receptors and their signaling pathways. Collectively, MOR and TRPV1 can mutually affect each other’s behavior and β-arrestin 2 apparently plays a key role in the bidirectional crosstalk between these two receptors in the plasma membrane.

An analgesic peptide H-20 attenuates chronic pain via the PD-1 pathway with few adverse effects

“…TRPV1, which responds to nociceptive stimuli such as elevated temperature, reduced pH, vanilloids, and other pain-inducing substances, is an important ion channel associated with peripheral sensitization to pain ( 15 , 21 – 23 ). The activation of TRPV1 with capsaicin markedly evoked the influx of extracellular calcium.…”

Age-Induced Changes in Mu Opioid Receptor Signaling in the Midbrain Periaqueductal Gray of Male and Female Rats

“…ERK1/2 phosphorylation stimulates the activity of Gα-interacting protein (GAIP), an RGS protein that acts as a GTPase activator to reduce opioid signaling at the level of G-protein activation (Ogier-Denis et al, 2000). Indeed, pharmacological inhibition of ERK1/2 phosphorylation in a rat model leads to improved morphine analgesia (Popiolek-Barczyk et al, 2014; Melkes et al, 2020). Thus, the age- and sex-induced changes in morphine potency may be driven in part by age-induced hyper-phosphorylation of ERK1/2 and result in the downregulation of G-protein signaling.…”

Repeated Morphine Administration Increases TRPV1 mRNA Expression and Autoradiographic Binding at Supraspinal Sites in the Pain Pathway

“…Interactions between µ-opioid receptors and TRPV1 were reported both in in vitro and in vivo studies. In addition, µ-opioid receptors and TRPV1 reciprocally regulated each other via the β-arrestin 2 signaling pathway in HEK293 cells ( Melkes et al ., 2020 ). The activation of the µ-opioid receptor induces sensitization of TRPV1 by sequestering β-arrestin-2 away from TRPV1, thus reducing the TRPV1/β-arrestin-2 association and increasing TRPV1 activity in sensory neurons ( Rowan et al ., 2014 ).…”