Proenkephalin A gene products activate a new family of sensory neuron–specific GPCRs

Abstract

Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities. This family of GPCRs is uniquely localized in the human and rat small sensory neuron, and we called this family the sensory neuron--specific G protein--coupled receptors (SNSRs). Receptors of the SNSR family are distinct from the traditional opioid receptors in their insensitivity to the classical opioid antagonist naloxone and poor activation by opioid ligands. The unique localization of SNSRs and their activation by proenkephalin A peptide fragments indicate a possible function for SNSRs in sensory neuron regulation and in the modulation of nociception.

Molecular restrictions for human eye irritation by chemical vapors

“…Without discarding a role for G protein-coupled receptors (GPCRs) (Dong et al, 2001;Lembo et al, 2002), already known to be major players in olfactory chemoreception (Firestein, 2004;Gaillard et al, 2004), the most likely candidates are members of the transient receptor potential (TRP) channel family (Clapham et al, 2001). Among them, vanilloid (e.g.…”

Human Sensory Neuron-specific Mas-related G Protein-coupled Receptors-X1 Sensitize and Directly Activate Transient Receptor Potential Cation Channel V1 via Distinct Signaling Pathways

“…Of particular interest are proteins that are highly enriched or exclusively expressed in primary sensory neurons, because specific modulation of these targets may allow circumvent untoward effects. Recently, Mas-related G protein-coupled receptors-X1 (MRGPR-X1) 2 have been shown to be exclusively expressed in primary sensory neurons and to be activated by bovine adrenal medulla peptide-8-22 (BAM8 -22) originating from proteolytic cleavage of pro-enkephalin by pro-hormone convertases (1,2). Several studies reported activation of the G q pathway by MRGPR-X1 in overexpression systems (1,(3)(4)(5), and a recent study revealed increased pain sensation in 15 healthy volunteers after BAM8 -22 application (6).…”

“…Recently, Mas-related G protein-coupled receptors-X1 (MRGPR-X1) 2 have been shown to be exclusively expressed in primary sensory neurons and to be activated by bovine adrenal medulla peptide-8-22 (BAM8 -22) originating from proteolytic cleavage of pro-enkephalin by pro-hormone convertases (1,2). Several studies reported activation of the G q pathway by MRGPR-X1 in overexpression systems (1,(3)(4)(5), and a recent study revealed increased pain sensation in 15 healthy volunteers after BAM8 -22 application (6). In contrast, overexpression of MRGPR-X1 in rat dorsal root ganglia (DRG) neurons resulted in BAM8 -22-mediated inhibition of voltage-gated calcium currents and activation of M-type potassium channels via G i/o proteins believed to blunt pain perception (7).…”

MrgX2 Is a High Potency Cortistatin Receptor Expressed in Dorsal Root Ganglion

“…Tissue distribution studies have shown these receptors to be expressed mainly in the small sensory neurons of the dorsal root ganglia (DRG), suggesting a role in nociception. To date, cognate ligands have been identified for five of these receptors: proenkephalin A gene products, especially BAM22 (EC 50 ϳ13 nM), have been shown to potently activate human MrgX1 (SNSR3) (9). The neuropeptide RF amides are agonists at murine MrgA1 (NPFF, EC 50 ϳ200 nM), MrgC11 (NPFF, EC 50 ϳ54 nM), and MrgA4 (NPAF, EC 50 ϳ60 nM) (10).…”