SLC41A1 Mg2+ transport is regulated via Mg2+-dependent endosomal recycling through its N-terminal cytoplasmic domain

2011 ◽  
Vol 439 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Tyler Mandt ◽  
Yumei Song ◽  
Andrew M. Scharenberg ◽  
Jaya Sahni
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Surface Expression ◽  
Cytoplasmic Domain ◽  
Transport Systems ◽  
Central Component ◽  
Transport Function ◽  
Endosomal Recycling ◽  
Transporter Expression

SLC41A1 (solute carrier family 41, member A1) is a recently described vertebrate member of the MgtE family of Mg2+ transporters. Although MgtE transporters are found in both prokaryotic and eukaryotic organisms, and are highly conserved, little is known about the regulation of their Mg2+ transport function. In the present study, we have shown that endogenous SLC41A1 transporter expression is post-transcriptionally regulated by extracellular Mg2+ in TRPM7 (transient receptor potential cation channel, subfamily M, member 7)-deficient cells, suggesting that SLC41A1 transporters underlie a novel plasma membrane Mg2+ transport function. Consistent with this conclusion, structure–function analyses of heterologous SLC41A1 transporter expression demonstrate that SLC41A1 transporters exhibit the same plasma membrane orientation as homologous bacterial MgtE proteins, are capable of complementing growth of TRPM7-deficient cells only when the Mg2+ transporting pore is intact, and require an N-terminal cytoplasmic domain for Mg2+-dependent regulation of lysosomal degradation and surface expression. Taken together, our results indicate that SLC41A1 proteins are a central component of vertebrate Mg2+ transport systems, and that their Mg2+ transport function is regulated primarily through an endosomal recycling mechanism involving the SLC41A1 N-terminal cytoplasmic domain.

scholarly journals Cellular cholesterol controls TRPC3 function: evidence from a novel dominant-negative knockdown strategy

2006 ◽  
Vol 396 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Annarita Graziani ◽  
Christian Rosker ◽  
Sepp D. Kohlwein ◽  
Michael X. Zhu ◽  
Christoph Romanin ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Lipid Membrane ◽  
Membrane Conductance ◽  
Receptor Potential ◽  
Surface Expression ◽  
Dominant Negative ◽  
Membrane Microdomains ◽  
Membrane Expression ◽  
Hek 293

TRPC3 (canonical transient receptor potential protein 3) has been suggested to be a component of cation channel complexes that are targeted to cholesterol-rich lipid membrane microdomains. In the present study, we investigated the potential role of membrane cholesterol as a regulator of cellular TRPC3 conductances. Functional experiments demonstrated that cholesterol loading activates a non-selective cation conductance and a Ca2+ entry pathway in TRPC3-overexpressing cells but not in wild-type HEK-293 (human embryonic kidney 293) cells. The cholesterol-induced membrane conductance exhibited a current-to-voltage relationship similar to that observed upon PLC (phospholipase C)-dependent activation of TRPC3 channels. Nonetheless, the cholesterol-activated conductance lacked negative modulation by extracellular Ca2+, a typical feature of agonist-activated TRPC3 currents. Involvement of TRPC3 in the cholesterol-dependent membrane conductance was further corroborated by a novel dominant-negative strategy for selective blockade of TRPC3 channel activity. Expression of a TRPC3 mutant, which contained a haemagglutinin epitope tag in the second extracellular loop, conferred antibody sensitivity to both the classical PLC-activated as well as the cholesterol-activated conductance in TRPC3-expressing cells. Moreover, cholesterol loading as well as PLC stimulation was found to increase surface expression of TRPC3. Promotion of TRPC3 membrane expression by cholesterol was persistent over 30 min, while PLC-mediated enhancement of plasma membrane expression of TRPC3 was transient in nature. We suggest the cholesterol content of the plasma membrane as a determinant of cellular TRPC3 activity and provide evidence for cholesterol dependence of TRPC3 surface expression.

scholarly journals Direct Interaction with Rab11a Targets the Epithelial Ca2+ Channels TRPV5 and TRPV6 to the Plasma Membrane

2006 ◽  
Vol 26 (1) ◽  
pp. 303-312 ◽  
Author(s):  
Stan F. J. van de Graaf ◽  
Qing Chang ◽  
Arjen R. Mensenkamp ◽  
Joost G. J. Hoenderop ◽  
René J. M. Bindels
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Specific Interaction ◽  
Direct Interaction ◽  
Receptor Potential ◽  
Surface Expression ◽  
The Body ◽  
Cell Surface Expression ◽  
Apical Plasma Membrane ◽  
Transient Receptor

ABSTRACT TRPV5 and TRPV6 are the most Ca2+-selective members of the transient receptor potential (TRP) family of cation channels and play a pivotal role in the maintenance of Ca2+ balance in the body. However, little is known about the mechanisms controlling the plasma membrane abundance of these channels to regulate epithelial Ca2+ transport. In this study, we demonstrated the direct and specific interaction of GDP-bound Rab11a with TRPV5 and TRPV6. Rab11a colocalized with TRPV5 and TRPV6 in vesicular structures underlying the apical plasma membrane of Ca2+-transporting epithelial cells. This GTPase recognized a conserved stretch in the carboxyl terminus of TRPV5 that is essential for channel trafficking. Furthermore, coexpression of GDP-locked Rab11a with TRPV5 or TRPV6 resulted in significantly decreased Ca2+ uptake, caused by diminished channel cell surface expression. Together, our data demonstrated the important role of Rab11a in the trafficking of TRPV5 and TRPV6. Rab11a exerts this function in a novel fashion, since it operates via direct cargo interaction while in the GDP-bound configuration.

scholarly journals Transcriptomic Profiling of Ca2+ Transport Systems during the Formation of the Cerebral Cortex in Mice

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1800
Author(s):  
Alexandre Bouron
Keyword(s):  
Cerebral Cortex ◽  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Transmembrane Protein ◽  
Receptor Potential ◽  
Cytosolic Calcium ◽  
Cation Channel ◽  
Transport Systems ◽  
Transcriptomic Profiling ◽  
Transient Receptor

Cytosolic calcium (Ca2+) transients control key neural processes, including neurogenesis, migration, the polarization and growth of neurons, and the establishment and maintenance of synaptic connections. They are thus involved in the development and formation of the neural system. In this study, a publicly available whole transcriptome sequencing (RNA-Seq) dataset was used to examine the expression of genes coding for putative plasma membrane and organellar Ca2+-transporting proteins (channels, pumps, exchangers, and transporters) during the formation of the cerebral cortex in mice. Four ages were considered: embryonic days 11 (E11), 13 (E13), and 17 (E17), and post-natal day 1 (PN1). This transcriptomic profiling was also combined with live-cell Ca2+ imaging recordings to assess the presence of functional Ca2+ transport systems in E13 neurons. The most important Ca2+ routes of the cortical wall at the onset of corticogenesis (E11–E13) were TACAN, GluK5, nAChR β2, Cav3.1, Orai3, transient receptor potential cation channel subfamily M member 7 (TRPM7) non-mitochondrial Na+/Ca2+ exchanger 2 (NCX2), and the connexins CX43/CX45/CX37. Hence, transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1), transmembrane protein 165 (TMEM165), and Ca2+ “leak” channels are prominent intracellular Ca2+ pathways. The Ca2+ pumps sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and plasma membrane Ca2+ ATPase 1 (PMCA1) control the resting basal Ca2+ levels. At the end of neurogenesis (E17 and onward), a more numerous and diverse population of Ca2+ uptake systems was observed. In addition to the actors listed above, prominent Ca2+-conducting systems of the cortical wall emerged, including acid-sensing ion channel 1 (ASIC1), Orai2, P2X2, and GluN1. Altogether, this study provides a detailed view of the pattern of expression of the main actors participating in the import, export, and release of Ca2+. This work can serve as a framework for further functional and mechanistic studies on Ca2+ signaling during cerebral cortex formation.

Inositol lipids and TRPC channel activation

2007 ◽  
Vol 74 ◽  
pp. 37-45 ◽  
Author(s):  
James W. Putney
Keyword(s):  
Plasma Membrane ◽  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Calcium Signalling ◽  
Receptor Potential ◽  
Breakdown Product ◽  
Channel Activation ◽  
Inositol Lipids ◽  
Transient Receptor ◽  
Secondary Mechanism

The original hypothesis put forth by Bob Michell in his seminal 1975 review held that inositol lipid breakdown was involved in the activation of plasma membrane calcium channels or ‘gates’. Subsequently, it was demonstrated that while the interposition of inositol lipid breakdown upstream of calcium signalling was correct, it was predominantly the release of Ca2+ that was activated, through the formation of Ins(1,4,5)P3. Ca2+ entry across the plasma membrane involved a secondary mechanism signalled in an unknown manner by depletion of intracellular Ca2+ stores. In recent years, however, additional non-store-operated mechanisms for Ca2+ entry have emerged. In many instances, these pathways involve homologues of the Drosophila trp (transient receptor potential) gene. In mammalian systems there are seven members of the TRP superfamily, designated TRPC1–TRPC7, which appear to be reasonably close structural and functional homologues of Drosophila TRP. Although these channels can sometimes function as store-operated channels, in the majority of instances they function as channels more directly linked to phospholipase C activity. Three members of this family, TRPC3, 6 and 7, are activated by the phosphoinositide breakdown product, diacylglycerol. Two others, TRPC4 and 5, are also activated as a consequence of phospholipase C activity, although the precise substrate or product molecules involved are still unclear. Thus the TRPCs represent a family of ion channels that are directly activated by inositol lipid breakdown, confirming Bob Michell's original prediction 30 years ago.

scholarly journals Diacylglycerol activates the influx of extracellular cations in T-lymphocytes independently of intracellular calcium-store depletion and possibly involving endogenous TRP6 gene products

2002 ◽  
Vol 364 (1) ◽  
pp. 245-254 ◽  
Author(s):  
Alessandra GAMBERUCCI ◽  
Emanuele GIURISATO ◽  
Paola PIZZO ◽  
Maristella TASSI ◽  
Roberta GIUNTI ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Transient Receptor Potential ◽  
Human Peripheral Blood ◽  
Receptor Potential ◽  
Animal Cells ◽  
Bivalent Cation ◽  
Intracellular Calcium Store ◽  
Transient Receptor

In Jurkat and human peripheral blood T-lymphocytes, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, activated the influx of Ca2+, Ba2+ and Sr2+. OAG also caused plasma-membrane depolarization in Ca2+-free media that was recovered by the addition of bivalent cation, indicating the activation of Na+ influx. OAG-induced cation influx was (i) mimicked by the natural dacylglycerol 1-stearoyl-2-arachidonyl-sn-glycerol, (ii) not blocked by inhibiting protein kinase C or in the absence of phopholipase C activity and (iii) blocked by La3+ and Gd3+. Differently from OAG, both thapsigargin and phytohaemagglutinin activated a potent influx of Ca2+, but little influx of Ba2+ and Sr2+. Moreover, the influx of Ca2+ activated by thapsigargin and that activated by OAG were additive. Furthermore, several drugs (i.e. econazole, SKF96365, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, 2-aminoethoxy diphenylborate and calyculin-A), while inhibiting the influx of Ca2+ induced by both thapsigargin and phytohaemagglutinin, did not affect OAG-stimulated cation influx. Transient receptor potential (TRP) 3 and TRP6 proteins have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann and Schultz (1999) Nature (London) 397, 259–263]. In both Jurkat and peripheral blood T-lymphocytes, mRNA encoding TRP proteins 1, 3, 4 and 6 was detected by reverse transcriptase PCR, and the TRP6 protein was detected by Western blotting in a purified plasma-membrane fraction. We conclude that T-cells express a diacylglycerol-activated cation channel, unrelated to the channel involved in capacitative Ca2+ entry, and associated with the expression of TRP6 protein.

scholarly journals Ultrastructural and immunohistochemical localization of plasma membrane Ca2+-ATPase 4 in Ca2+-transporting epithelia

2015 ◽  
Vol 309 (7) ◽  
pp. F604-F616 ◽  
Author(s):  
R. Todd Alexander ◽  
Megan R. Beggs ◽  
Reza Zamani ◽  
Niels Marcussen ◽  
Sebastian Frische ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Basolateral Membrane ◽  
Receptor Potential ◽  
Human Kidney ◽  
Muscle Layer ◽  
Transient Receptor Potential Vanilloid ◽  
Distal Nephron

Plasma membrane Ca2+-ATPases (PMCAs) participate in epithelial Ca2+ transport and intracellular Ca2+ signaling. The Pmca4 isoform is enriched in distal nephron isolates and decreased in mice lacking the epithelial transient receptor potential vanilloid 5 Ca2+ channel. We therefore hypothesized that Pmca4 plays a significant role in transcellular Ca2+ flux and investigated the localization and regulation of Pmca4 in Ca2+-transporting epithelia. Using antibodies directed specifically against Pmca4, we found it expressed only in the smooth muscle layer of mouse and human intestines, whereas pan-specific Pmca antibodies detected Pmca1 in lateral membranes of enterocytes. In the kidney, Pmca4 showed broad localization to the distal nephron. In the mouse, expression was most abundant in segments coexpressing the epithelial ransient receptor potential vanilloid 5 Ca2+ channel. Significant, albeit lower, expression was also evident in the region encompassing the cortical thick ascending limbs, macula densa, and early distal tubules as well as smooth muscle layers surrounding renal vessels. In the human kidney, a similar pattern of distribution was observed, with the highest PMCA4 expression in Na+-Cl− cotransporter-positive tubules. Electron microscopy demonstrated Pmca4 localization in distal nephron cells at both the basolateral membrane and intracellular perinuclear compartments but not submembranous vesicles, suggesting rapid trafficking to the plasma membrane is unlikely to occur in vivo. Pmca4 expression was not altered by perturbations in Ca2+ balance, pointing to a housekeeping function of the pump in Ca2+-transporting epithelia. In conclusion, Pmca4 shows a divergent expression pattern in Ca2+-transporting epithelia, inferring diverse roles for this isoform not limited to transepithelial Ca2+ transport.

scholarly journals Analgesic Effects of Lipid Raft Disruption by Sphingomyelinase and Myriocin via Transient Receptor Potential Vanilloid 1 and Transient Receptor Potential Ankyrin 1 Ion Channel Modulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Ádám Horváth ◽  
Maja Payrits ◽  
Anita Steib ◽  
Boglárka Kántás ◽  
Tünde Biró-Süt ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Membrane Microdomains ◽  
Neuronal Cultures ◽  
Transient Receptor Potential Vanilloid ◽  
Peripheral Sensitization ◽  
Transient Receptor

Transient Receptor Potential (TRP) Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons, and integratively regulate nociceptor and inflammatory functions. Lipid rafts are liquid-ordered plasma membrane microdomains rich in cholesterol, sphingomyelin and gangliosides. We earlier showed that lipid raft disruption inhibits TRPV1 and TRPA1 functions in primary sensory neuronal cultures. Here we investigated the effects of sphingomyelinase (SMase) cleaving membrane sphingomyelin and myriocin (Myr) prohibiting sphingolipid synthesis in mouse pain models of different mechanisms. SMase (50 mU) or Myr (1 mM) pretreatment significantly decreased TRPV1 activation (capsaicin)-induced nocifensive eye-wiping movements by 37 and 41%, respectively. Intraplantar pretreatment by both compounds significantly diminished TRPV1 stimulation (resiniferatoxin)-evoked thermal allodynia developing mainly by peripheral sensitization. SMase (50 mU) also decreased mechanical hyperalgesia related to both peripheral and central sensitizations. SMase (50 mU) significantly reduced TRPA1 activation (formalin)-induced acute nocifensive behaviors by 64% in the second, neurogenic inflammatory phase. Myr, but not SMase altered the plasma membrane polarity related to the cholesterol composition as shown by fluorescence spectroscopy. These are the first in vivo results showing that sphingolipids play a key role in lipid raft integrity around nociceptive TRP channels, their activation and pain sensation. It is concluded that local SMase administration might open novel perspective for analgesic therapy.

scholarly journals Intracellular pools of DAG-activated TRPC3 channels are essential for TLR4 activation

2021 ◽  
Author(s):  
Javier Casas ◽  
Clara Meana ◽  
José Ramón López-López ◽  
Jesús Balsinde ◽  
María A. Balboa
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Central Component ◽  
Lps Challenge ◽  
Intracellular Sensing ◽  
Lipin 1 ◽  
Transient Receptor ◽  
Tlr4 Activation

ABSTRACTToll-like receptor 4, the receptor for bacterial lipopolysaccharide (LPS), drives inflammatory responses that protect against pathogens and boost the adaptive immunity. LPS responses are known to depend on calcium fluxes, but the molecular mechanisms involved are poorly understood. Here we present evidence that the transient receptor potential canonical channel 3 (TRPC3) is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this way TRPC3 participates in cytosolic Ca2+ elevations, TLR4 endocytosis, activation of inflammatory transcription factors and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol (DAG) generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells show reduced Ca2+ responses to LPS challenge. A cameleon indicator directed to the endoplasmic reticulum shows that this is the organelle from which TRPC3 mediates the Ca2+ release. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3.

scholarly journals Functional characterization of transient receptor potential channels in mouse urothelial cells

2010 ◽  
Vol 298 (3) ◽  
pp. F692-F701 ◽  
Author(s):  
Wouter Everaerts ◽  
Joris Vriens ◽  
Grzegorz Owsianik ◽  
Giovanni Appendino ◽  
Thomas Voets ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Patch Clamp ◽  
Calcium Imaging ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Sensory Function ◽  
Trp Channel ◽  
Urothelial Cells ◽  
Transient Receptor

The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4−/− mice were isolated, cultured (12–48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction.

scholarly journals Cryo-EM structure of the cytoplasmic domain of murine transient receptor potential cation channel subfamily C member 6 (TRPC6)

2018 ◽  
Vol 293 (26) ◽  
pp. 10381-10391 ◽  
Author(s):  
Caleigh M. Azumaya ◽  
Francisco Sierra-Valdez ◽  
Julio F. Cordero-Morales ◽  
Terunaga Nakagawa
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cytoplasmic Domain ◽  
Cation Channel ◽  
Transient Receptor
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