Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, in particular the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb neurons, and we demonstrate that Nppb/somatostatin-cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch, and characterize a contrasting anti-nociceptive role for the peptide.
Highlights d Chemogenetic activation of mast cells induces itch responses d Receptors for mast cell mediators are specifically expressed by Nppb neurons d Serotonin, leukotriene, and sphingosine-1-phosphate stimulate Nppb neurons d Mast cell activation via GRP spinal cord signaling elicits itch behavior
In the last two decades, the urokinase-type plasminogen activator receptor (uPAR) has been implicated in a number of human pathologies such as cancer, bacterial infections, and paroxysmal nocturnal hemoglobinuria. The primary function of this glycolipid-anchored receptor is to focalize uPA-mediated plasminogen activation at the cell surface, which is accomplished by its high-affinity interaction with the growth factor-like domain of uPA. Detailed insights into the molecular basis underlying the interactions between uPAR and its two bona fide ligands, uPA and vitronectin, have been obtained recently by X-ray crystallography and surface plasmon resonance studies. Importantly, these structural studies also define possible druggable target sites in uPAR for small molecules and provide guidelines for the development of reporter groups applicable for non-invasive molecular imaging of uPAR expression in vivo by positron emission tomography. In this review, we will discuss recent advances in our perception of the structure-function relationships of uPAR ligation and how these may assist translational research in preclinical intervention studies of uPAR function.
The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the -hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the -hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.Timely controlled cell migration is a decisive factor for a plethora of important biological processes that occur during development and adulthood. Controlled cell migration is thus intimately involved in both maintenance and dynamic remodeling of tissue architectures during, e.g. wound healing and mammary gland development (1). These processes are executed and tightly regulated via a complicated cross-talk between specific cell surface receptors (e.g. integrins) and insoluble protein components deposited in the extracellular matrix. The extracellular matrix is nonetheless thought to play a dual role in regulating cell migration, as it provides both the focal adhesion sites required for cellular traction and opposes migration by generating physical barriers (2, 3). Cell migration in vivo, therefore, requires a coordinated regulation of extracellular matrix proteolysis, adhesion, and signaling (4). The urokinase-type plasminogen activator receptor (uPAR) 2 may allegedly assist a rendezvous between these functions, as it has the potential to exert control at all three levels. Besides being responsible for focalizing uPA-mediated plasminogen activation on cell surfaces (5-7), uPAR also facilitates adherence to vitronectin embedded in the extracellular matrix (8 -10), and as a consequence, it promotes intracellular signaling (4, 11).The glycolipid-anchored uPAR is a modular glycoprotein composed of three homologous Ly6/uPAR-type (LU) protein domain repeats (5, 12). The far majority of proteins belonging to this domain family contain only a single copy of the LU module, as exemplified by the glycolipid-anchored CD59, the extracellular ligand binding domain in the TGF- receptors, and the diverse group of secreted snake venom ␣-neurotoxins (13). In the human genome, five genes are recognized so far to encode proteins with multiple LU domains, and these are all confined to a small ...
Background:The urokinase receptor (uPAR) acts as a modulator of lamellipodia formation on vitronectin-rich matrices. Results: Constraining the flexibility of uPAR by an interdomain cross-link drives it into a constitutively active state. Conclusion: Conformational dynamics of uPAR is important for its function and is regulated by uPA binding. Significance: This flexibility needs to be considered when investigating and targeting the function of uPAR.
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