Lanthanides Potentiate TRPC5 Currents by an Action at Extracellular Sites Close to the Pore Mouth

Jung, Silke; Mühle, Anja; Schaefer, Michael; Strotmann, Rainer; Schultz, Günter; Plant, Tim

doi:10.1074/jbc.m211484200

Cited by 234 publications

(258 citation statements)

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“…1A), consistent with the presence and absence of this effect in the two isoforms, respectively (10,11,13). It was also shown (see above) that there is striking similarity between the H ϩ and lanthanoid effects on TRPC4, TRPC5, and TRPC6, indicating that the glutamate residues Glu 543 and Glu 595 may also play a role in the H ϩ sensitivity of TRPC5.…”

Section: Sequence Alignment Of the Poresupporting

confidence: 62%

“…Most other TRP channels, with the exception of TRPV1 (see below), and other Ca 2ϩ -permeable cation channels, including voltage-gated Ca 2ϩ channels (14), are inhibited by micromolar concentrations of lanthanoids. In contrast to the potentiation of TRPC5 with micromolar concentrations of La 3ϩ and Gd 3ϩ , millimolar concentrations cause inhibition (13). At the single channel level, the potentiatory and inhibitory effects of La 3ϩ and Gd 3ϩ overlap, with potentiation (an increase in channel open probability) dominating over inhibition (a decrease in conductance) at micromolar concentrations.…”

mentioning

confidence: 91%

“…The isolation of the mouse TRPC5 coding sequence from brain total RNA (10), the introduction of the point mutations E543Q and E595Q/E598Q (13) and fusion of these cDNAs with the YFP gene (17) are described in the respective publications. The YFPtagged versions were used in the experiments summarized in Figs.…”

Section: Methodsmentioning

confidence: 99%

“…For TRPC5, additional activators have been described, the physiological significance of which is uncertain (7)(8)(9). A surprising feature of TRPC4 and TRPC5 and heteromultimeric combinations of TRPC1 and TRPC5 is their strong potentiation (10 -13) or activation (7) by micromolar concentrations of the trivalent lanthanoid cations La 3ϩ and Gd 3ϩ , effects also seen for TRPC5 with millimolar Ca 2ϩ (7,13). Most other TRP channels, with the exception of TRPV1 (see below), and other Ca 2ϩ -permeable cation channels, including voltage-gated Ca 2ϩ channels (14), are inhibited by micromolar concentrations of lanthanoids.…”

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confidence: 99%

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Potentiation of TRPC5 by Protons

Semtner

Schaefer

Pinkenburg

et al. 2007

Journal of Biological Chemistry

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Mammalian members of the classical transient receptor potential channel subfamily (TRPC) are Ca 2؉ -permeable cation channels involved in receptor-mediated increases in intracellular Ca 2؉ . TRPC4 and TRPC5 form a group within the TRPC subfamily and are activated in a phospholipase C-dependent manner by an unidentified messenger. Unlike most other Ca 2؉ -permeable channels, TRPC4 and -5 are potentiated by micromolar concentrations of La 3؉ and Gd 3؉ . This effect results from an action of the cations at two glutamate residues accessible from the extracellular solution. Here, we show that TRPC4 and -5 respond to changes in extracellular pH. Lowering the pH increased both G protein-activated and spontaneous TRPC5 currents. Both effects were already observed with small reductions in pH (from 7.4 to 7.0) and increased up to pH 6.5. TRPC4 was also potentiated by decreases in pH, whereas TRPC6 was only inhibited, with a pIC 50 of 5.7. Mutation of the glutamate residues responsible for lanthanoid sensitivity of TRPC5 (E543Q and E595Q) modified the potentiation of TRPC5 by acid. Further evidence for a similarity in the actions of lanthanoids and H ؉ on TRPC5 is the reduction in single channel conductance and dramatic increase in channel open probability in the presence of either H ؉ or Gd 3؉ that leads to larger integral currents. In conclusion, the high sensitivity of TRPC5 to H ؉ indicates that, in addition to regulation by phospholipase C and other factors, the channel may act as a sensor of pH that links decreases in extracellular pH to Ca 2؉ entry and depolarization.The TRP 2 ion channel family consists of over 25 proteins that are homologous to Drosophila TRP. Like many other cation channels, TRP channels are proposed to have six transmembrane segments (S1-S6) with a re-entrant pore-forming loop between S5 and S6, and intracellular C and N termini (for reviews, see Refs. 1-5). In addition to the transmembrane topology, a number of other structural features are shared between subfamilies. Thus, TRPC, TRPV, and TRPM channels have a characteristic sequence, the TRP box (Fig. 1B), not far from S6 in their cytosolic C termini, and often have regulatory calmodulin-binding domains in the C-terminal tail. TRPC, TRPV, and TRPA channels have N-terminal, cytosolic ankyrinlike repeats, the functional role of which is still unclear. TRP channels also share functional features. Where channel activity has been demonstrated, TRP channels have been shown to be cation channels with relative Ca 2ϩ permeabilities (P Ca /P Na ) ranging from low (TRPM4 and -5) to high (TRPV5 and -6). Many TRP channels are regulated by phospholipase C (PLC)-dependent mechanisms, including members of the TRPC subfamily, which show PLC-dependent activation, and some TRP channels from other subfamilies, which display PLC-dependent modulation or activation.TRPC4 and TRPC5 are receptor-operated, PLC-dependent, Ca 2ϩ -permeable nonselective cation channels. However, in contrast to several other members of the TRPC subfamily that are activated by diacylglycer...

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Section: Sequence Alignment Of the Poresupporting

confidence: 62%

mentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Potentiation of TRPC5 by Protons

Semtner

Schaefer

Pinkenburg

et al. 2007

Journal of Biological Chemistry

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“…However, the mechanism behind this peculiar effect and the reason it has not been observed until now remain unclear. La 3ϩ , which, like RR, appears to interact with the pore regions of certain nonselective cation channels, can augment current responses through TRPC4 and TRPC5 (32). It remains to be determined, however, whether the phenomenon we observe with RR represents a similar effect and whether it is attributable to the association of TRPV4 with cell type-specific proteins, posttranslational modifications, the secondary activation of a distinct conductance, or the particular conditions of our recordings.…”

Section: Discussionmentioning

confidence: 64%

Warm Temperatures Activate TRPV4 in Mouse 308 Keratinocytes

Chung¹,

Lee²,

Caterina³

2003

Journal of Biological Chemistry

260

211

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Mammalian survival requires constant monitoring of environmental and body temperature. Recently, several members of the transient receptor potential vanilloid (TRPV) subfamily of ion channels have been identified that can be gated by increases in temperature into the warm (TRPV3 and TRPV4) or painfully hot (TRPV1 and TRPV2) range. In rodents, TRPV3 and TRPV4 proteins have not been detected in sensory neurons but are highly expressed in skin epidermal keratinocytes. Here, we show that in response to warm temperatures (>32°C), the mouse 308 keratinocyte cell line exhibits nonselective transmembrane cationic currents and Ca 2؉ influx. Both TRPV3 and TRPV4 are expressed in 308 cells. However, the warmth-evoked responses we observe most closely resemble those mediated by recombinant TRPV4 on the basis of their electrophysiological properties and sensitivity to osmolarity and the phorbol ester, 4␣-phorbol-12,13-didecanoate. Together, these data support the notion that keratinocytes are capable of detecting modest temperature elevations, strongly suggest that TRPV4 participates in these responses, and define a system for the cell biological analysis of warmth transduction.The perception of ambient temperature is a physiological process critical to the maintenance of body temperature and the avoidance of painful or dangerous thermal extremes. Since the identification of the heat-sensing ion channel TRPV1 (1), 1 which is activated by temperatures above 42°C, there has been a significant focus on potential thermosensory functions for this and other ion channels of the transient receptor potential family. TRPV2 (2) and TRPV3 (3-5) were first described as heat transducers operative at very hot (Ͼ52°C) and moderately warm (Ͼ34°C) temperatures, respectively. TRPV4, which was originally identified as an osmosensory ion channel (6 -9), can also be activated by warm temperatures (Ͼ34°C) (10, 11). In addition, two TRP proteins outside of the TRPV subfamily, TRPM8 (12, 13) and ANKTM1 (ankyrin repeat/transmembrane-containing ion channel) (14), have been identified as cold-activated ion channels expressed in sensory neurons.In mammals, the skin is extremely important for the transduction of thermal information and its transmission to the central nervous system. Cutaneous thermosensation has been largely attributed to the sensory nerves that innervate the dermal and epidermal layers of the skin. Recent reports, however, have suggested the possibility that other skin components, most notably keratinocytes, might also participate in temperature sensation. TRPV1 and TRPV2 are highly expressed in distinct subsets of sensory neurons (2). In humans, TRPV3 is also expressed in sensory neurons (5). In contrast, attempts to detect TRPV4 (9, 10) and TRPV3 (3) at the protein level in rodent sensory neurons have been unsuccessful. Rather, immunohistochemical studies of mouse and rat skin have revealed that keratinocytes exhibit the greatest degree of cutaneous TRPV3 (3) and TRPV4 (10) expression. In addition, although peripheral sensory neurons ...

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TRPChannels

Gees

Owsianik

Nilius

et al. 2012

Comprehensive Physiology

148

120

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TRP channels constitute a large superfamily of cation channel forming proteins, all related to the gene product of the transient receptor potential (trp) locus in Drosophila. In mammals, 28 different TRP channel genes have been identified, which exhibit a large variety of functional properties and play diverse cellular and physiological roles. In this article, we provide a brief and systematic summary of expression, function, and (patho)physiological role of the mammalian TRP channels.

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Lanthanides Potentiate TRPC5 Currents by an Action at Extracellular Sites Close to the Pore Mouth

Cited by 234 publications

References 50 publications

Potentiation of TRPC5 by Protons

Potentiation of TRPC5 by Protons

Warm Temperatures Activate TRPV4 in Mouse 308 Keratinocytes

TRPChannels

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