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1.
JCI Insight ; 5(2)2020 01 30.
Article in English | MEDLINE | ID: mdl-31846440

ABSTRACT

Vision loss in age-related macular degeneration (AMD) stems from disruption of photoreceptor cells in the macula, the central retinal area required for high-acuity vision. Mice and rats have no macula, but surgical insertion of a subretinal implant can induce localized photoreceptor degeneration due to chronic separation from retinal pigment epithelium, simulating a key aspect of AMD. We find that the implant-induced loss of photoreceptors in rat retina leads to local changes in the physiology of downstream retinal ganglion cells (RGCs), similar to changes in RGCs of rodent models of retinitis pigmentosa (RP), an inherited disease causing retina-wide photoreceptor degeneration. The local implant-induced changes in RGCs include enhanced intrinsic excitability leading to accelerated spontaneous firing, increased membrane permeability to fluorescent dyes, and enhanced photosensitization by azobenzene photoswitches. The local physiological changes are correlated with an increase in retinoic acid receptor-induced (RAR-induced) gene transcription, the key process underlying retinal remodeling in mouse models of RP. Hence the loss of photoreceptors, whether by local physical perturbation or by inherited mutation, leads to a stereotypical set of pathophysiological consequences in RGCs. These findings implicate RAR as a possible common therapeutic target for reversing the signal-corrupting effects of retinal remodeling in both RP and AMD.


Subject(s)
Macular Degeneration/pathology , Neuronal Plasticity/physiology , Retina/pathology , Retinal Degeneration/pathology , Retinal Neurons/pathology , Animals , Disease Models, Animal , Mice , Prostheses and Implants/adverse effects , Rats , Receptors, Retinoic Acid , Retina/diagnostic imaging , Retinal Degeneration/diagnostic imaging , Retinal Ganglion Cells/pathology , Retinitis Pigmentosa/pathology
2.
Neuron ; 102(3): 574-586.e5, 2019 05 08.
Article in English | MEDLINE | ID: mdl-30876849

ABSTRACT

Light responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Retinitis pigmentosa (RP) is a blinding disease caused by photoreceptor degeneration, depriving downstream neurons of light-sensitive input. Photoreceptor degeneration also triggers hyperactive firing of RGCs, obscuring light responses initiated by surviving photoreceptors. Here we show that retinoic acid (RA), signaling through its receptor (RAR), is the trigger for hyperactivity. A genetically encoded reporter shows elevated RAR signaling in degenerated retinas from murine RP models. Enhancing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas. Drug inhibition of RAR reduces hyperactivity in degenerating retinas and unmasks light responses in RGCs. Gene therapy inhibition of RAR increases innate and learned light-elicited behaviors in vision-impaired mice. Identification of RAR as the trigger for hyperactivity presents a degeneration-dependent therapeutic target for enhancing low vision in RP and other blinding disorders.


Subject(s)
Receptors, Retinoic Acid/antagonists & inhibitors , Retinal Degeneration/metabolism , Retinal Ganglion Cells/metabolism , Tretinoin/metabolism , Vision, Ocular , Animals , Cell Membrane Permeability , Disease Models, Animal , Electroencephalography , Genetic Therapy , HEK293 Cells , Humans , Mice , Patch-Clamp Techniques , Photosensitivity Disorders/metabolism , Rats , Receptors, Retinoic Acid/genetics , Retinitis Pigmentosa/metabolism
3.
Neuron ; 92(1): 100-113, 2016 Oct 05.
Article in English | MEDLINE | ID: mdl-27667006

ABSTRACT

Azobenzene photoswitches confer light sensitivity onto retinal ganglion cells (RGCs) in blind mice, making these compounds promising candidates as vision-restoring drugs in humans with degenerative blindness. Remarkably, photosensitization manifests only in animals with photoreceptor degeneration and is absent from those with intact rods and cones. Here we show that P2X receptors mediate the entry of photoswitches into RGCs, where they associate with voltage-gated ion channels, enabling light to control action-potential firing. All charged photoswitch compounds require permeation through P2X receptors, whose gene expression is upregulated in the blind retina. Photoswitches and membrane-impermeant fluorescent dyes likewise penetrate through P2X receptors to label a subset of RGCs in the degenerated retina. Electrophysiological recordings and mapping of fluorescently labeled RGC dendritic projections together indicate that photosensitization is highly selective for OFF-RGCs. Hence, P2X receptors are a natural conduit allowing cell-type-selective and degeneration-specific delivery of photoswitches to restore visual function in blinding disease.


Subject(s)
Azo Compounds/pharmacology , Blindness , Retina/drug effects , Retina/physiology , Vision, Ocular/drug effects , Vision, Ocular/physiology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Azo Compounds/pharmacokinetics , Blindness/physiopathology , Ion Channels/metabolism , Mice , Photic Stimulation , Photoreceptor Cells/drug effects , Photoreceptor Cells/physiology , Photosensitivity Disorders/chemically induced , Photosensitivity Disorders/metabolism , Photosensitizing Agents/pharmacokinetics , Photosensitizing Agents/pharmacology , Receptors, Purinergic P2X/biosynthesis , Receptors, Purinergic P2X/physiology , Retina/cytology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/physiology
4.
Nat Commun ; 5: 3125, 2014.
Article in English | MEDLINE | ID: mdl-24445575

ABSTRACT

Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.


Subject(s)
Lipopolysaccharides/adverse effects , Neurogenic Inflammation/metabolism , Pain/metabolism , Transient Receptor Potential Channels/metabolism , Animals , CHO Cells , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Cricetulus , Escherichia coli/chemistry , HEK293 Cells , Humans , Ion Channel Gating/drug effects , Lipid A/chemistry , Membrane Potentials/drug effects , Mice, Inbred C57BL , Mice, Knockout , Neurogenic Inflammation/pathology , Neuropeptides/metabolism , Nociceptors/metabolism , Pain/pathology , Sensory Receptor Cells/drug effects , Signal Transduction/drug effects , TRPA1 Cation Channel , Toll-Like Receptor 4/metabolism , Transient Receptor Potential Channels/agonists
5.
Nat Cell Biol ; 14(8): 851-8, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22750945

ABSTRACT

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit Gα(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gα(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Gα(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Gα(q) protein, but not Gßγ, potently inhibits TRPM8 in excised patches. We conclude that Gα(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.


Subject(s)
Cold Temperature , Neurons/metabolism , TRPM Cation Channels/antagonists & inhibitors , TRPM Cation Channels/metabolism , Animals , Cells, Cultured , Crystallography, X-Ray , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Humans , Mice , Mice, Inbred C57BL , Models, Molecular , Neurons/cytology , Protein Binding , Signal Transduction
6.
Curr Pharm Biotechnol ; 12(1): 3-11, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20932263

ABSTRACT

Transient Receptor Potential channels are exquisite molecular transducers of multiple physical and chemical stimuli, hence the raising interest to study their relevance to Sensory Biology. Here we discuss a number of aspects of the biophysical and pharmacological properties of TRP channels, which we consider essential for a clear understanding of their sensory function in vivo. By examining concrete examples extracted from recent literature we illustrate that TRP channel research is a field in motion, and that many established dogmas on biophysical properties, drug specificity and physiological role are continuously reshaped, and sometimes even dismantled.


Subject(s)
Drug Discovery/methods , Sensation/physiology , Transient Receptor Potential Channels/chemistry , Transient Receptor Potential Channels/physiology , Humans , Transient Receptor Potential Channels/agonists , Transient Receptor Potential Channels/antagonists & inhibitors
7.
Proc Natl Acad Sci U S A ; 106(38): 16451-6, 2009 Sep 22.
Article in English | MEDLINE | ID: mdl-19805319

ABSTRACT

Peripheral interactions between nociceptive fibers and mast cells contribute to inflammatory pain, but little is known about mechanisms mediating neuro-immune communication. Here we show that metalloproteinase MT5-MMP (MMP-24) is an essential mediator of peripheral thermal nociception and inflammatory hyperalgesia. We report that MT5-MMP is expressed by CGRP-containing peptidergic nociceptors in dorsal root ganglia and that Mmp24-deficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions. Consistently, mutant peptidergic sensory neurons hyperinnervate the skin, a phenotype that correlates with changes in the regulated cleavage of the cell-cell adhesion molecule N-cadherin. In contrast to basal nociception, Mmp24(-/-) mice do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. Collectively, our findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that this metalloproteinase may be a target for pain control.


Subject(s)
Ganglia, Spinal/metabolism , Hyperalgesia/physiopathology , Matrix Metalloproteinases, Membrane-Associated/metabolism , Nociceptors/metabolism , Animals , Blotting, Western , COS Cells , Cadherins/metabolism , Cell Line, Tumor , Cells, Cultured , Chlorocebus aethiops , Female , Fluorescent Antibody Technique , Ganglia, Spinal/cytology , Hot Temperature , Humans , Hyperalgesia/genetics , Hyperalgesia/metabolism , Inflammation/genetics , Inflammation/metabolism , Inflammation/physiopathology , Male , Matrix Metalloproteinases, Membrane-Associated/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Transfection
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