scholarly journals Kv2 channel/AMIGO β-subunit assembly modulates both channel function and cell adhesion molecule surface trafficking

2021 ◽  
Author(s):  
Emily E. Maverick ◽  
Ashley N. Leek ◽  
Michael M. Tamkun
Keyword(s):  
Plasma Membranes ◽  
Delayed Rectifier ◽  
Β Subunit ◽  
Membrane Excitability ◽  
Membrane Contact Sites ◽  
Membrane Contact ◽  
Regulatory Effects ◽  
Channel Properties ◽  
Fine Tune ◽  
Molecule Surface

The Kv2 channels encode delayed rectifier currents that regulate membrane potential in many tissues. They also have a non-conducting function to form stable junctions between the endoplasmic reticulum and plasma membranes, creating membrane contact sites that mediate functions distinct from membrane excitability. Therefore, proteins that interact with Kv2.1 and Kv2.2 channels can alter conducting and/or non-conducting channel properties. One member of the AMIGO family of proteins is an auxiliary β-subunit for Kv2 channels and modulates Kv2.1 electrical activity. However, the AMIGO family has two additional members of ∼50% similarity that have not yet been characterized as Kv2 β-subunits. In this work we show that the surface trafficking and localization of all three AMIGOs are controlled by their assembly with both Kv2 channels. Additionally, assembly of each AMIGO with either Kv2.1 or Kv2.2 hyperpolarizes the channel activation midpoint by -10 mV. However, only AMIGO2 significantly slows inactivation and deactivation, leading to a prolonged open state of Kv2 channels. The co-regulatory effects of Kv2s and AMIGOs likely fine-tune both electrical and non-electrical properties of cells in which they are expressed.

scholarly journals Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

2019 ◽  
Vol 77 (14) ◽  
pp. 2839-2857 ◽  
Author(s):  
Elsa Meneses-Salas ◽  
Ana García-Melero ◽  
Kristiina Kanerva ◽  
Patricia Blanco-Muñoz ◽  
Frederic Morales-Paytuvi ◽  
...  
Keyword(s):  
Late Endosome ◽  
Dependent Manner ◽  
Lipid Transfer ◽  
Cholesterol Accumulation ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Membrane Contact ◽  
Domain 3 ◽  
Niemann Pick ◽  
Mutant Cells

Abstract Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.

scholarly journals Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽  
2021 ◽  
Author(s):  
Christopher A Piggott ◽  
Zilu Wu ◽  
Stephen Nurrish ◽  
Suhong Xu ◽  
Joshua M Kaplan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Tissue Specific ◽  
Voltage Gated ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Pharyngeal Muscles ◽  
Membrane Contact ◽  
Null Mutants

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

scholarly journals Remodelling of Nucleus-Vacuole Junctions During Metabolic and Proteostatic Stress

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110166
Author(s):  
Verena Kohler ◽  
Sabrina Büttner
Keyword(s):  
Nuclear Envelope ◽  
Internal Stress ◽  
Molecular Architecture ◽  
Adaptation To Stress ◽  
Semipermeable Membranes ◽  
Cellular Adaptation ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Intracellular Compartments ◽  
Membrane Contact

Cellular adaptation to stress and metabolic cues requires a coordinated response of different intracellular compartments, separated by semipermeable membranes. One way to facilitate interorganellar communication is via membrane contact sites, physical bridges between opposing organellar membranes formed by an array of tethering machineries. These contact sites are highly dynamic and establish an interconnected organellar network able to quickly respond to external and internal stress by changing size, abundance and molecular architecture. Here, we discuss recent work on nucleus-vacuole junctions, connecting yeast vacuoles with the nucleus. Appearing as small, single foci in mitotic cells, these contacts expand into one enlarged patch upon nutrient exhaustion and entry into quiescence or can be shaped into multiple large foci essential to sustain viability upon proteostatic stress at the nuclear envelope. We highlight the remarkable plasticity and rapid remodelling of these contact sites upon metabolic or proteostatic stress and their emerging importance for cellular fitness.

scholarly journals Synaptotagmins at the endoplasmic reticulum–plasma membrane contact sites maintain diacylglycerol homeostasis during abiotic stress

2021 ◽  
Author(s):  
Noemi Ruiz-Lopez ◽  
Jessica Pérez-Sancho ◽  
Alicia Esteban del Valle ◽  
Richard P Haslam ◽  
Steffen Vanneste ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Abiotic Stress ◽  
Fluorescent Protein ◽  
Mechanical Damage ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Green Fluorescent

Abstract Endoplasmic reticulum-plasma membrane contact sites (ER-PM CS) play fundamental roles in all eukaryotic cells. Arabidopsis thaliana mutants lacking the ER-PM protein tether synaptotagmin1 (SYT1) exhibit decreased plasma membrane (PM) integrity under multiple abiotic stresses such as freezing, high salt, osmotic stress and mechanical damage. Here, we show that, together with SYT1, the stress-induced SYT3 is an ER-PM tether that also functions in maintaining PM integrity. The ER-PM CS localization of SYT1 and SYT3 is dependent on PM phosphatidylinositol-4-phosphate and is regulated by abiotic stress. Lipidomic analysis revealed that cold stress increased the accumulation of diacylglycerol at the PM in a syt1/3 double mutant relative to wild type while the levels of most glycerolipid species remain unchanged. Additionally, the SYT1-green fluorescent protein (GFP) fusion preferentially binds diacylglycerol in vivo with little affinity for polar glycerolipids. Our work uncovers a SYT-dependent mechanism of stress adaptation counteracting the detrimental accumulation of diacylglycerol at the PM produced during episodes of abiotic stress.

Regulation and physiology of membrane contact sites

2021 ◽  
Vol 71 ◽  
pp. 148-157
Author(s):  
Rossella Venditti ◽  
Cathal Wilson ◽  
Maria Antonietta De Matteis
Keyword(s):  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact

scholarly journals Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110265
Author(s):  
Vladimir Zhemkov ◽  
Jen Liou ◽  
Ilya Bezprozvanny
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Composition ◽  
Sigma 1 Receptor ◽  
Functional Roles ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Sigma 1 ◽  
Membrane Contact ◽  
Organelle Communication ◽  
Cellular Organelles

Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains.

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