The Adhesion GPCR Latrophilin/CIRL Shapes Mechanosensation

Scholz, Nicole; Gehring, Jennifer; Guan, Chonglin; Ljaschenko, Dmitrij; Fischer, Robin; Lakshmanan, Vetrivel; Kittel, Robert J.; Langenhan, Tobias

doi:10.1016/j.celrep.2015.04.008

Cited by 150 publications

(184 citation statements)

References 49 publications

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“…1B) (Scholz et al, 2015). Genetic experiments further demonstrated that Latrophilin/dCirl activity may regulate the input-output function of mechanosensory nerve cells through the modulation of transient receptor potential channels, which ultimately govern the electrical response of these neurons (Scholz et al, 2015).…”

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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The study of G protein-coupled receptors (GPCRs) has benefited greatly from experimental approaches that interrogate their functions in controlled, artificial environments. Working in vitro, GPCR receptorologists discovered the basic biologic mechanisms by which GPCRs operate, including their eponymous capacity to couple to G proteins; their molecular makeup, including the famed serpentine transmembrane unit; and ultimately, their three-dimensional structure. Although the insights gained from working outside the native environments of GPCRs have allowed for the collection of low-noise data, such approaches cannot directly address a receptor's native (in vivo) functions. An in vivo approach can complement the rigor of in vitro approaches: as studied in model organisms, it imposes physiologic constraints on receptor action and thus allows investigators to deduce the most salient features of receptor function. Here, we briefly discuss specific examples in which model organisms have successfully contributed to the elucidation of signals controlled through GPCRs and other surface receptor systems. We list recent examples that have served either in the initial discovery of GPCR signaling concepts or in their fuller definition. Furthermore, we selectively highlight experimental advantages, shortcomings, and tools of each model organism.

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Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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“…For GPR126 in peripheral nervous system development, Stachel exposure may require interaction with the ECM molecule Laminin-211, which directs subsequent mechanical activation as proposed by Petersen et al (2015). Mechanical stimulation of aGPCR has also been suggested for Latrophilin/CIRL in sensory neurons (Scholz et al, 2015), while other studies have shown a direct activation of aGPCRs through interactions with collagens (Luo et al, 2014;Paavola et al, 2014).…”

Section: In Vitro Pharmacology Of Agpcrsmentioning

confidence: 98%

“…Complementary evidence for mechanical activation of aGPCR signals in vivo comes from recent studies on the ADGRL homolog Latrophilin/CIRL of the vinegar fly D. melanogaster (Scholz et al, 2015). Here, the aGPCR is resident in mechanosensory neurons, which-upon mechanical stimulation through sound, touch, or stretch-respond adequately with an increase in electrical activity.…”

Section: In Vivo Mechanisms Of Agpcr Activationmentioning

confidence: 99%

Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

et al. 2015

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The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in humans. aGPCRs are characterized by their enormous size and complex modular structures. While the physiologic importance of many aGPCRs has been clearly demonstrated in recent years, the underlying molecular functions have only recently begun to be elucidated. In this minireview, we present an overview of our current knowledge on aGPCR activation and signal transduction with a focus on the latest findings regarding the interplay between ligand binding, mechanical force, and the tethered agonistic Stachel sequence, as well as implications on translational approaches that may derive from understanding aGPCR pharmacology.

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“…An emerging concept is that ECM proteins mechanically modulate signaling properties of adhesion GPCRs [11,22,25], and in the future it will be interesting to understand how different ECM signals converge to control Gpr126/Adgrg6 signaling. In humans, mutations in LAMA2, encoding the α2 chain of Laminin-211, cause merosin-deficient congenital muscular dystrophy (MDC1A) with dysmyelination [26][27][28], suggesting that modulation of GPR126/ADGRG6 might be efficacious in these patients.…”

Section: Schwann Cell Developmentmentioning

confidence: 99%

G Protein-Coupled Receptors in Myelinating Glia

Mogha¹,

D’Rozario²,

Monk

2017

Trends in Pharmacological Sciences

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The G protein-coupled receptor (GPCR) super-family represents the largest class of functionally selective drug targets for disease modulation and therapy. GPCRs have been studied in great detail in central nervous system (CNS) neurons, yet these important molecules have been relatively understudied in glia. In recent years, however, exciting new roles for GPCRs in glial cell biology have emerged. Here, we focus on key roles for GPCRs in a specialized subset of glia, myelinating glia. We highlight recent work firmly establishing GPCRs as regulators of myelinating glial cell development and myelin repair. These advancements expand our understanding of myelinating glial cell biology and underscore the utility of targeting GPCRs to promote myelin repair in human disease. KeywordsG protein-coupled receptor (GPCR); myelination; Schwann cell; oligodendrocyte; remyelination An overview of G protein-coupled receptors in the nervous systemThe G protein-coupled receptor (GPCR) super-family of seven transmembrane (7TM) receptors comprises the largest class of cell membrane receptors [1]. GPCRs are activated by myriad stimuli including peptides, hormones, light, proteolytic processing of their Ntermini, small molecules, and more traditional protein ligands [2,3]. GPCRs have emerged as major pharmacological drug targets due to their key roles in a variety of physiological functions in disease and health, and GPCR modulators represent at least one-third of all clinically marketed drugs [4]. GPCRs can be classified into five families using the phylogenetically based GRAFS system: glutamate, rhodopsin, adhesion, frizzled, and secretin [5]. Glutamate is a major excitatory neurotransmitter in the nervous system, and * Correspondence: monkk@wustl.edu (K.R. Monk). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing conflicts. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript accordingly, glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and development of neuronal circuits [6,7]. The rhodopsin family has by far the greatest number of GPCRs, and members are involved in photoreception and neurotransmission [5]. Frizzled GPCRs are activated by wingless/int (Wnt) proteins and control numerous cellular processes including neural crest development, patterning and adult neurogenesis [8]. Secretin receptors are classic hormone receptors, some of which have neuroprotective functions in the central nervou...

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The Adhesion GPCR Latrophilin/CIRL Shapes Mechanosensation

Cited by 150 publications

References 49 publications

Model Organisms in G Protein–Coupled Receptor Research

Model Organisms in G Protein–Coupled Receptor Research

Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

G Protein-Coupled Receptors in Myelinating Glia

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