scholarly journals TRPC3 is a major contributor to functional heterogeneity of cerebellar Purkinje cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Bin Wu ◽  
François GC Blot ◽  
Aaron Benson Wong ◽  
Catarina Osório ◽  
Youri Adolfs ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Eyeblink Conditioning ◽  
Receptor Potential ◽  
Cellular Heterogeneity ◽  
Major Contributor ◽  
Loss Of Function ◽  
Functional Heterogeneity ◽  
Physiological Properties ◽  
Transient Receptor ◽  
Cerebellar Purkinje Cells

Despite the canonical homogeneous character of its organization, the cerebellum plays differential computational roles in distinct sensorimotor behaviors. Previously, we showed that Purkinje cell (PC) activity differs between zebrin-negative (Z–) and zebrin-positive (Z+) modules (Zhou et al., 2014). Here, using gain-of-function and loss-of-function mouse models, we show that transient receptor potential cation channel C3 (TRPC3) controls the simple spike activity of Z–, but not Z+ PCs. In addition, TRPC3 regulates complex spike rate and their interaction with simple spikes, exclusively in Z– PCs. At the behavioral level, TRPC3 loss-of-function mice show impaired eyeblink conditioning, which is related to Z– modules, whereas compensatory eye movement adaptation, linked to Z+ modules, is intact. Together, our results indicate that TRPC3 is a major contributor to the cellular heterogeneity that introduces distinct physiological properties in PCs, conjuring functional heterogeneity in cerebellar sensorimotor integration.

scholarly journals TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

2018 ◽  
Author(s):  
Bin Wu ◽  
Francois G.C. Blot ◽  
Aaron B. Wong ◽  
Catarina Osório ◽  
Youri Adolfs ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Transient Receptor Potential ◽  
Eyeblink Conditioning ◽  
Receptor Potential ◽  
Cellular Heterogeneity ◽  
Loss Of Function ◽  
Functional Heterogeneity ◽  
Homogeneous Population ◽  
Cerebellar Purkinje Cells

AbstractDespite the canonical homogenous character of its organization, the cerebellum plays differential computational roles in distinct types of sensorimotor behaviors. However, the molecular and cell physiological underpinnings are unclear. Here we determined the contribution of transient receptor potential cation channel type C3 (TRPC3) to signal processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z–), but not of zebrin-positive (Z+), Purkinje cells. Moreover, in vivo TRPC3 also regulated complex spike firing and its interaction with simple spikes exclusively in Z– Purkinje cells. Finally, we found that eyeblink conditioning, related to Z– modules, but not compensatory eye movement adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring functional heterogeneity in cerebellar sensorimotor integration.

scholarly journals Dissecting independent channel and scaffolding roles of the Drosophila transient receptor potential channel

2005 ◽  
Vol 171 (4) ◽  
pp. 685-694 ◽  
Author(s):  
Tao Wang ◽  
Yuchen Jiao ◽  
Craig Montell
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Loss Of Function ◽  
Visual Transduction ◽  
Channel Function ◽  
Transient Receptor ◽  
The Impact

Drosophila transient receptor potential (TRP) serves dual roles as a cation channel and as a molecular anchor for the PDZ protein, INAD (inactivation no afterpotential D). Null mutations in trp cause impairment of visual transduction, mislocalization of INAD, and retinal degeneration. However, the impact of specifically altering TRP channel function is not known because existing loss-of-function alleles greatly reduce protein expression. In the current study we describe the isolation of a set of new trp alleles, including trp14 with an amino acid substitution juxtaposed to the TRP domain. The trp14 flies stably express TRP and display normal molecular anchoring, but defective channel function. Elimination of the anchoring function alone in trpΔ1272, had minor effects on retinal morphology whereas disruption of channel function caused profound light-induced cell death. This retinal degeneration was greatly suppressed by elimination of the Na+/Ca2+ exchanger, CalX, indicating that the cell death was due primarily to deficient Ca2+ entry rather than disruption of the TRP-anchoring function.

scholarly journals Regulatory switch at the cytoplasmic interface controls TRPV channel gating

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lejla Zubcevic ◽  
William F Borschel ◽  
Allen L Hsu ◽  
Mario J Borgnia ◽  
Seok-Yong Lee
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Physiological Processes ◽  
Physiological Properties ◽  
Electrophysiological Studies ◽  
Transient Receptor ◽  
Large Rearrangements

Temperature-sensitive transient receptor potential vanilloid (thermoTRPV) channels are activated by ligands and heat, and are involved in various physiological processes. ThermoTRPV channels possess a large cytoplasmic ring consisting of N-terminal ankyrin repeat domains (ARD) and C-terminal domains (CTD). The cytoplasmic inter-protomer interface is unique and consists of a CTD coiled around a β-sheet which makes contacts with the neighboring ARD. Despite much existing evidence that the cytoplasmic ring is important for thermoTRPV function, the mechanism by which this unique structure is involved in thermoTRPV gating has not been clear. Here, we present cryo-EM and electrophysiological studies which demonstrate that TRPV3 gating involves large rearrangements at the cytoplasmic inter-protomer interface and that this motion triggers coupling between cytoplasmic and transmembrane domains, priming the channel for opening. Furthermore, our studies unveil the role of this interface in the distinct biophysical and physiological properties of individual thermoTRPV subtypes.

scholarly journals Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors

2011 ◽  
Vol 192 (4) ◽  
pp. 557-567 ◽  
Author(s):  
Ikuko Yonamine ◽  
Takeshi Bamba ◽  
Niraj K. Nirala ◽  
Nahid Jesmin ◽  
Teresa Kosakowska-Cholody ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Endosomal Trafficking ◽  
Loss Of Function ◽  
Late Endosomes ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Transient Receptor ◽  
G Protein Coupled

Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein–coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP.

scholarly journals A REVIEW ON ROLE OF TRPV CATION CHANNELS

2021 ◽  
Vol 10 (2) ◽  
pp. 32-51
Author(s):  
Deep Sharma ◽  
Rekha Rana ◽  
Kiran Thakur
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channels ◽  
Cellular Functions ◽  
Physiological Properties ◽  
Transient Receptor

The mammalian branch of the Transient Receptor Potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’) and the TRPA (‘Ankyrin’) group. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/ reabsorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiological properties of all TRPV members in the light of various cellular functions of these channels and their significance in the various diseases.

scholarly journals Loss of Function of Transient Receptor Potential Vanilloid 1 (TRPV1) Genetic Variant Is Associated with Lower Risk of Active Childhood Asthma

2010 ◽  
Vol 285 (36) ◽  
pp. 27532-27535 ◽  
Author(s):  
Gerard Cantero-Recasens ◽  
Juan R. Gonzalez ◽  
César Fandos ◽  
Enric Duran-Tauleria ◽  
Lidwien A. M. Smit ◽  
...  
Keyword(s):  
Childhood Asthma ◽  
Lower Risk ◽  
Transient Receptor Potential ◽  
Genetic Variant ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Loss Of Function ◽  
Transient Receptor

scholarly journals A competing hydrophobic tug on L596 to the membrane core unlatches S4–S5 linker elbow from TRP helix and allows TRPV4 channel to open

2016 ◽  
Vol 113 (42) ◽  
pp. 11847-11852 ◽  
Author(s):  
Jinfeng Teng ◽  
Stephen H. Loukin ◽  
Andriy Anishkin ◽  
Ching Kung
Keyword(s):  
Transient Receptor Potential ◽  
Specific Interaction ◽  
Receptor Potential ◽  
Yeast Cells ◽  
Transient Receptor Potential Vanilloid ◽  
Loss Of Function ◽  
Open Probability ◽  
Outward Currents ◽  
Transient Receptor ◽  
Dynamics Simulations

We have some generalized physical understanding of how ion channels interact with surrounding lipids but few detailed descriptions on how interactions of particular amino acids with contacting lipids may regulate gating. Here we discovered a structure-specific interaction between an amino acid and inner-leaflet lipid that governs the gating transformations of TRPV4 (transient receptor potential vanilloid type 4). Many cation channels use a S4–S5 linker to transmit stimuli to the gate. At the start of TRPV4’s linker helix is leucine 596. A hydrogen bond between the indole of W733 of the TRP helix and the backbone oxygen of L596 secures the helix/linker contact, which acts as a latch maintaining channel closure. The modeled side chain of L596 interacts with the inner lipid leaflet near the polar–nonpolar interface in our model—an interaction that we explored by mutagenesis. We examined the outward currents of TRPV4-expressing Xenopus oocyte upon depolarizations as well as phenotypes of expressing yeast cells. Making this residue less hydrophobic (L596A/G/W/Q/K) reduces open probability [Po; loss-of-function (LOF)], likely due to altered interactions at the polar–nonpolar interface. L596I raises Po [gain-of-function (GOF)], apparently by placing its methyl group further inward and receiving stronger water repulsion. Molecular dynamics simulations showed that the distance between the levels of α-carbons of H-bonded residues L596 and W733 is shortened in the LOFs and lengthened in the GOFs, strengthening or weakening the linker/TRP helix latch, respectively. These results highlight that L596 lipid attraction counteracts the latch bond in a tug-of-war to tune the Po of TRPV4.

scholarly journals Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

2021 ◽  
Author(s):  
Albert Misko ◽  
Laura D Weinstock ◽  
Sitara B Sankar ◽  
Amanda Furness ◽  
Yulia Grishchuk ◽  
...  
Keyword(s):  
Motor Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Brief Assessment ◽  
Blood Cytokines ◽  
Mucolipidosis Iv ◽  
Transient Receptor

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss-of-function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.

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