Mechanisms of Compartmentalized Expression of Mrg Class G-Protein-Coupled Sensory Receptors

Abstract

Mrg class G-protein-coupled receptors (GPCRs) are expressed exclusively in sensory neurons in the trigeminal and dorsal root ganglia. Pharmacological activation of Mrg proteins is capable of modulating sensory neuron activities and elicits nociceptive effects. In this study, we illustrate a control mechanism that allows the Runx1 runt domain transcription factor to generate compartmentalized expression of these sensory GPCRs. Expression of MrgA, MrgB, and MrgC subclasses is confined to an "A/B/C" neuronal compartment that expresses Runx1 transiently (or does not express Runx1), whereas MrgD expression is restricted to a "D" compartment with persistent Runx1 expression.

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

“…Defined nociceptor subtypes have been termed C-fiber (C-) or Aδ-fiber (A-) mechanoheat nociceptors (MHNs), mechanical nociceptors (MNs), mechanically insensitive (MI) or sensitive afferents, and mechanoheat-cold nociceptors [5,6]. The molecular properties of DRG neurons have been extensively studied, including their expression of various receptors and ion channels such as neuropeptide Y (NPY) receptors [7], MAS-related G-protein-coupled receptors (MRGPRs) [8,9], voltage-gated Na + channels [10], transient receptor potential (TRP) channels [11,12], ATP receptors [13], acid-sensing ion channels (ASICs) [14,15] and tyrosine kinase receptors (TRKs) [16]. Gene expression profiles of DRG tissue have been also analyzed by microarray and RNA-sequencing (RNA-seq) techniques [17,18].…”

Hepatocyte Growth Factor-Met Signaling Is Required forRunx1Extinction and Peptidergic Differentiation in Primary Nociceptive Neurons

“…Given the mutually repressive activity of Met and RUNX1, nociceptors coexpressing these two factors might be transient and rapidly segregate either into Met ϩ peptidergic (if Met signaling is strong enough to extinguish Runx1 expression) or into TrkA ϩ /Ret ϩ neurons (if RUNX1 activity is strong enough to repress Met expression). An alternative hypothesis is that RUNX1 might change its transcriptional activity during development; at early stages, it might act as an activator (e.g., positively controlling Trp channels, Ret, and Met expression), whereas, later on, it might switch to a repressive state (e.g., negatively controlling CGRP), as previously shown for Mrg receptors (Liu et al, 2008). Finally, one could imagine that additional factors might participate in this process.…”

Pharmacology and Signaling of MAS-Related G Protein–Coupled Receptors

“…The initial discovery of the MRGPR family pointed to a selective expression of MRGPR in primary sensory neurons derived from the TrkA + population (Dong et al, 2001). Perinatally, this results in a largely overlapping MRGPRA to -D expression in the same population of neurons (Dong et al, 2001;Zylka et al, 2003;Liu et al, 2008). After birth, TrkA expression ceases in roughly half of the formerly TrkA + neurons (Molliver et al, 1997).…”

“…Instead of TrkA, these cells start to express c-ret, the receptor of the glial-derived neurotrophic factor (Molliver et al, 1997). In adulthood, expression of all MRGPR is maintained in c-ret + , but not in the remaining TrkA + neurons (Dong et al, 2001;Zylka et al, 2003;Liu et al, 2008). Interestingly, despite the largely overlapping expression pattern of all MRGPR in perinatal primary sensory neurons, in adulthood most MRGPR subtypes are not coexpressed in the same c-ret + population and exhibit a compartmentalized expression pattern in distinct subpopulations (Dong et al, 2001;Zylka et al, 2003;Liu et al, 2008).…”