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.
Highlights
Large numbers of studies conducted over the previous decades have increased knowledge of pain mechanisms at both the cellular and molecular level
MOR is linked to the inhibitory G proteins, whose major signaling pathway leads to inhibition of adenylyl cyclase or modulation of mitogen activated protein kinases (MAPKs)
The expression and plasma membrane localization of TRPV1 and MOR is shown in Figure 2A,B, respectively
Summary
Large numbers of studies conducted over the previous decades have increased knowledge of pain mechanisms at both the cellular and molecular level. MOR belongs to the family of G protein-coupled receptors (GPCRs). MOR is linked to the inhibitory G proteins, whose major signaling pathway leads to inhibition of adenylyl cyclase or modulation of mitogen activated protein kinases (MAPKs). The properties of these receptors and their signaling systems have been extensively studied in connection with nociception and with a potential risk of tolerance and dependence associated with long-term use or abuse of opioids [3,4,5]. It has been observed that MOR-initiated signaling can be modulated by other GPCRs or some ion channels. In the case of antinociception, communication between the MOR and TRPV1 (transient receptor potential vanilloid 1) receptors appears noteworthy [6,7]
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