| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SYMPOSIUM REPORT |
1 Departments of Pharmacology
2 Medicine, University College London, London, WC1E 6BT, UK
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 17 March 2007;
accepted after revision 28 March 2007;
first published online 29 March 2007)
Corresponding author D. A. Brown: Department of Pharmacology, University College London, London, WC1E 6BT, UK. Email: d.a.brown{at}ucl.ac.uk
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
|
|
An important property of M-channels is that they can be closed by activating a number of Gq/11-coupled neurotransmitter receptors (Brown, 1988; Marrion, 1997) – prototypically (but far from exclusively) by muscarinic acetylcholine receptors (mAChRs; hence the name M-channel) (Fig. 2A). This leads to an enhanced excitability (Fig. 2B). When the receptors are activated by synaptically released acetylcholine, there is an accompanying slow depolarizing excitatory postsynaptic potential (Adams & Brown, 1982). The mechanisms for Gq/11-mediated inhibition are discussed further below.
Activation of Kv7/M-channels by PIP2
Though ‘gated’ by voltage, like many other ion channels (Suh & Hille, 2005), Kv7/M-channels require membrane PIP2 to open (Fig. 3A). Thus, Kv7.2 + 7.3 channels in membrane patches rapidly shut down on excision and then re-open on applying phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2 or ‘PIP2’) or dioctanoyl-PIP2 (diC8-PIP2) to the inner surface (Zhang et al. 2003; Li et al. 2005). Individual subunits vary widely in their sensitivity to diC8-PIP2 (Li et al. 2005), in a manner that correlates with their different maximal open probabilities in cell-attached mode (Li et al. 2004), suggesting that the latter is determined by the resting membrane level of PIP2. In support of this, Kv7.2/7.3 currents are reduced when PIP2 is depleted by targeted membrane insertion of a polyphosphate-5-phosphatase and Kv7 currents enhanced in a subunit-dependent manner by increased membrane phosphatidylinositol-4-5-kinase (PI(4)5-K) (Suh et al. 2006).
|
Mechanism of M-current inhibition by muscarinic receptor activation: PIP2 depletion
Muscarinic receptor activation clearly stimulates PIP2 hydrolysis in sympathetic neurons (see Brown, 1988; Marrion, 1997; Bofill-Cardona et al. 2000; Winks et al. 2005). Further, in cell-attached patch recording, both native M-channels (Selyanko et al. 1992; Marrion, 1993) and expressed Kv7.2 + Kv7.3 channels (Selyanko et al. 2000) enclosed within the patch are inhibited by stimulating muscarinic receptor outside the patch, suggestive of some form of ‘diffusible messenger’. Assuming (not unreasonably) that this messenger passes from the receptors to the channels, early experiments concentrated on the two principal products of PIP2 hydrolysis, inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), and on the respective subsequent events, Ca2+ release and protein kinase C (PKC) activation (see Marrion, 1997). However, it now seems unlikely that either pathway is primarily or solely responsible for muscarinic inhibition (Cruzblanca et al. 1998; Suh & Hille, 2006), although Kv7 channel phosphorylation by the DAG/PKC system appears to exert an essential ‘sensitizing’ role, facilitated by a channel-associated A-kinase anchoring protein (AKAP) that also binds PKC (Hoshi et al. 2003, 2005).
Instead, given the importance of PIP2 for channel activity (see above), the principal cause of channel closure is now thought to be the reduction in membrane PIP2 that accompanies Gq-PLC activation and subsequent PIP2 hydrolysis (Suh & Hille, 2002; Zhang et al. 2003; Suh et al. 2004) (Fig. 3B). Indeed, for expressed Kv7.2 + Kv7.3 channels, the dynamics and extent of channel inhibition by M1-mAChRs can be quantitatively accounted for in terms of changes in PIP2 (Suh et al. 2004; Horowitz et al. 2005), and the dependence of inhibition on PIP2 levels has recently been strengthened (Suh et al. 2006). Available evidence suggests that the same mechanism operates for M1-mAChR-induced inhibition of native M-channels in neurons (Suh & Hille, 2002; Zhang et al. 2003). For example, inhibition is reduced, rather than enhanced, when membrane PIP2 levels are increased by over-expressing the synthesizing enzyme PI4(5)-K (Winks et al. 2005), which would be expected if inhibition were due to the loss of PIP2 but not if it were due to a downstream product of PIP2 hydrolysis.
M-current inhibition by bradykinin: Ca2+ release
However, this scenario does not necessarily apply to all forms of receptor-mediated inhibition. Thus, in the case of at least two other receptor agonists – bradykinin and UTP – there is strong evidence that the primary cause of inhibition is the release of Ca2+ from intracellular stores by the IP3 generated by PIP2 hydrolysis (Cruzblanca et al. 1997; Bofill-Cardona et al. 2000; Shapiro & Zaika, 2007) (Fig. 3C). First, intracellular Ca2+ is known to inhibit M-channels, with an IC50 of 
100 nM (Selyanko & Brown, 1996), an effect mediated through activation of channel-attached calmodulin (Gamper & Shapiro, 2003). Second (and unlike the muscarinic receptors), stimulation of bradykinin receptors produces a small but clear increase in intracellular Ca2+ (Cruzblanca et al. 1997). This is because the receptors are closely coupled to the IP3 receptors, whereas the muscarinic receptors are not (Delmas et al. 2002). Nevertheless, a door (or channel) is either open or shut (de Musset, 1845), so why is it not shut already by the loss of PIP2? The suggested answer (Gamper et al. 2004; Winks et al. 2005) is that bradykinin does not reduce PIP2 because it also stimulates PIP2 synthesis, possibly by Ca2+ activation of neuronal calcium sensor-1 (NCS-1) and consequent activation of PI(4)-K; such a stimulation has been detected in neuroblastoma cells (Loew, 2007).
Tracking changes in membrane PIP2 in neurons
The question then arises: can we measure receptor-induced changes in membrane PIP2 in the sympathetic neuron in such a manner that allows them to be related to the various forms of receptor-induced M-channel inhibition?
In previous experiments we attempted to do this in single dissociated sympathetic neurons by observing the membrane-to-cytosol translocation of the GFP-tagged PH-domain of PLC
1 (PLC-PH-GFP) (Winks et al. 2005). This construct binds to the polar head-groups of PI(4,5)P2 in the membrane inner leaflet and then translocates to the cytosol when PIP2 is hydrolysed (Stauffer et al. 1998; Varnai & Balla, 1998) (Fig. 4A). In our experiments, muscarinic AChR activation induced a substantial membrane-to-cytosol translocation of PLC-PH-GFP that showed a close correlation with M-current inhibition in time-course (Fig. 4B and C) and also in agonist concentration dependence (Winks et al. 2005). However, since PLC-PH also binds to cytosolic IP3 (Hirose et al. 1999), PLC-PH-GFP translocation only provides a measure of overall PI(4,5)P2 hydrolysis, and is not a direct measure of the reduction in membrane PI(4,5)P2 concentration. We tried to correct for IP3 binding (and hence estimate changes in PIP2 concentration) using an intracellular IP3 displacement assay; our corrected data suggested a maximal depletion of 83%
– in line with measurements in various cell lines (Willars et al. 1998; Li et al. 2005; Horowitz et al. 2005). As an indirect method, however, this estimate is subject to considerable uncertainty, and, importantly, does not make any allowance for changes in the rate of PIP2 synthesis during receptor-induced hydrolysis. Thus, in the experiments of Winks et al. (2005), bradykinin produced as great a translocation of PLC-PH-GFP as did the muscarinic agonist, oxotremorine-M, even though M-current inhibition by bradykinin is thought not to result from PIP2 depletion (see above).
|
-PH-GFP construct that it binds to PIP2 but not to IP3 or other downstream products of PIP2 hydrolysis such as DAG or Ca2+, and hence can be used to monitor PIP2 changes alone. Although it also binds to several membrane phosphatidyl polyphosphates, including PI(4,5)P2, PI(3,4)P2 and PI(3,4,5)P3 (but not to PI(3,5)P2, PI(4)P or PI), changes in PI(4,5)P2 are by far the most substantial on stimulating Gq-coupled receptors (Willars et al. 1998; McLaughlin et al. 2002). We found that the yellow fluorescent protein (YFP)-tagged tubby construct tubby-R332H-cYFP co-localized in the outer membrane with the PLC-PH construct, and that the two co-translocated to the cytosol with a similar time-course on stimulating mAChRs with oxotremorine-M (thus verifying that mAChR-stimulation does indeed reduce membrane PIP2 levels in these cells). However, there was a major difference between the response of the two indicators to stimulating bradykinin receptors: although bradykinin produced as large a translocation of PLC-PH-GFP as did oxotremorine-M, it only produced about one-quarter of the tubby-R332H-cYFP translocation signal induced by oxotremorine-M (Fig. 5). This would accord with previous suggestions that bradykinin might stimulate PIP2 synthesis, thus limiting PIP2 depletion. Indeed, when synthesis was blocked with wortmannin, then the tubby translocation signals by bradykinin and oxotremorine-M were comparable (Fig. 5).
|
60% (Fig. 6A and B), in line with previous reports (Cruzblanca et al. 1997; Bofill-Cardona et al. 2000). Subsequent addition of wortmannin then restored full inhibition by bradykinin, to a level matching that produced by oxotremorine-M (Fig. 6C). This recapitulates the experiments of Gamper et al. (2004) who showed that wortmannin sensitized the normally insensitive N-type Ca2+ channels to bradykinin, but with the difference that the Ca2+ channels are not inhibited by Ca2+, whereas M-channels are. Thus, in the latter case, we have not simply enhanced a PIP2 depletion-dependent inhibition, but have switched the mechanism of inhibition entirely, from one produced primarily by a product of PIP2 hydrolysis (Fig. 3C) to one dependent on PIP2 itself (Fig. 3D). We say ‘primarily’ because bradykinin clearly does produce some PIP2 depletion, as judged from its effect on tubby translocation – probably enough to generate some 10–20% inhibition of M-current, even in the absence of a Ca2+ signal; this may account for the incomplete effect of thapsigargin in preventing inhibition. Hence, it seems that the two mechanisms co-exist, and indeed their proportionate significance might well vary under different metabolic conditions or between different cell types.
|
|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Adams PR & Brown DA (1982). Synaptic inhibition of the M-current: slow excitatory postsynaptic mechanism in bullfrog sympathetic neurones. J Physiol 332, 263–272.
Bofill-Cardona E, Vartian N, Nanoff C, Freissmuth M & Boehm S (2000). Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides. Mol Pharmacol 57, 1165–1172.
Brown DA (1988). M currents. In Ion Channels, vol. 1, pp. 55–99, ed. Narahashi T. Plenum Press, New York.
Brown DA & Adams PR (1980). Muscarinic suppression of a novel voltage-sensitive K+-current in a vertebrate neurone. Nature 283, 673–676.[CrossRef][Medline]
Brown DA & Constanti A (1980). Intracellular observations on the effects of muscarinic agonists on rat sympathetic neurones. Br J Pharmacol 70, 593–608.[Medline]
Brown DA, Selyanko AA, Hadley JK & Tatulian L (2002). Some pharmacological properties of neural KCNQ channels. Neurophysiology 34, 91–95.[CrossRef]
Brown SG, Thomas A, Dekker LV, Tinker A & Leaney J (2005). Protein kinase C- sensitizes Kir3.1/3.2 to changes in membrane phospholipid levels following M3 receptor activation in HEK293 cells. Am J Physiol Cell Physiol 289, C543–C556.
Cruzblanca H, Koh DS & Hille B (1998). Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons. Proc Natl Acad Sci U S A 95, 7151–7156.
de Musset A (1845). Il Faut Qu'une Porte Soit Ouverte Ou Fermée. Charpentier, Paris.
Delmas P & Brown DA (2005). Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 6, 850–862.[CrossRef][Medline]
Delmas P, Crest M & Brown DA (2004). Functional organization of PLC signaling microdomains in neurons. Trends Neurosci 27, 41–47.[CrossRef][Medline]
Delmas P, Wanaverbecq N, Abogadie FC, Mistry M & Brown DA (2002). Signaling microdomains define the specificity of receptor-mediated InsP3 pathways in neurons. Neuron 34, 209–220.[CrossRef][Medline]
Du X, Zhang H, Lopes C, Mirshahi T, Rohacs T & Logothetis DE (2004). Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of Kir channels by diverse modulators. J Biol Chem 279, 37271–37281.
Ford CP, Stemkowski PL, Light PE & Smith PA (2003). Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J Neurosci 23, 4931–4941.
Gamper N, Reznikov V, Yamada Y, Yang J & Shapiro MS (2004). Phosphatidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J Neurosci 24, 10980–10992.
Gamper N & Shapiro MS (2003). Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels. J Gen Physiol 122, 17–31.
Hadley JK, Passmore GM, Tatulian L, Al-Qatari M, Ye F, Wickenden AD & Brown DA (2003). Stoichiometry of expressed KCNQ2/KCNQ3 channels and subunit composition of native ganglionic M-channels deduced from block by tetraethylammonium (TEA). J Neurosci 23, 5012–5019.
Hirose K, Kadowaki S, Tanabe M, Takeshima H & Iino M (1999). Spatiotemporal dynamics of inositol 1,4,5-trisphosphate that underlies complex Ca2+ mobilization patterns. Science 284, 1527–1530.
Horowitz LF, Hirdes W, Suh BC, Hilgemann DW, Mackie K & Hille B (2005). Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol 126, 243–262.
Hoshi N, Langeberg LK & Scott JD (2005). Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nat Cell Biol 7, 1066–1073.[CrossRef][Medline]
Hoshi N, Zhang JS, Omaki M, Takeuchi T, Yokoyama S, Wanaverbecq N, Langeberg LK, Yoneda Y, Scott JD, Brown DA & Higashida H (2003). AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nat Neurosci 6, 564–571.[CrossRef][Medline]
Hughes S, Marsh SJ, Tinker A & Brown DA (2007). PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons. Pflugers Arch DOI: 10.1007/500424-007-0259-6.
Jentsch TJ (2000). Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci 1, 21–30.[CrossRef][Medline]
Keselman I & Logothetis D (2007). Diverse signalling pathways regulate Kir3 activity through modulation of channel interactions with PI (4,5) P2. Biophys J Abstract P-120-Plat.
Li Y, Gamper N, Hilgemann DW & Shapiro MS (2005). Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci 25, 9825–9835.
Li Y, Gamper N & Shapiro MS (2004). Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J Neurosci 24, 5079–5090.
Loew LM (2007). Where does all the PIP2 come from? J Physiol 582, 945–951 DOI: 10.1113/jphysiol.2007.132860
McLaughlin S, Wang J, Gambhir A & Murray D (2002). PIP2 and proteins: interactions, organization and information flow. Ann Rev Biophys Biomol Struct 31, 151–175.[CrossRef][Medline]
Marrion NV (1993). Selective reduction of one mode of M-channel gating by muscarine in sympathetic neurons. Neuron 11, 77–84.[CrossRef][Medline]
Marrion NV (1997). Control of M-current. Ann Rev Physiol 59, 483–504.[CrossRef][Medline]
Marrion NV, Smart TG, Marsh SJ & Brown DA (1989). Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype. Br J Pharmacol 98, 557–573.[Medline]
Quinn KV & Tinker AW (2004). Using domains from the protein tubby to report changes in PIP2 concentration in living cells. J Physiol 557P, PC92.
Robbins J, Marsh SJ & Brown DA (2006). Probing the regulation of M (Kv7) potassium channels in intact neurons with membrane-targeted peptides. J Neurosci 26, 7950–7961.
Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG & Shapiro L (2001). G protein signaling through tubby proteins. Science 292, 2041–2050.
Schwarz JR, Glassmeier G, Cooper E, Kao T, Nodera H, Tabuena D, Kaji R & Bostock H (2006). KCNQ channels mediate IKs, a slow K+ current regulating excitability in the node of Ranvier. J Physiol 573, 17–34.
Selyanko AA & Brown DA (1996). Intracellular calcium directly inhibits potassium M channels in excised membrane patches from rat sympathetic neurons. Neuron 16, 151–162.[CrossRef][Medline]
Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ & Brown DA (2000). Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol 522, 349–355.
Selyanko AA, Stansfeld CE & Brown DA (1992). Closure of potassium M-channels by muscarinic acetylcholine-receptor stimulants requires a diffusible messenger. Proc Roy Soc Series B 250, 119–125.[CrossRef]
Shah MM, Mistry M, Marsh SJ, Brown DA & Delmas P (2002). Molecular correlates of the M-current in cultured rat hippocampal neurons. J Physiol 544, 29–37.
Shapiro M & Zaika O (2007). Purinergic modulation of neuronal M-current involves IP3-mediated Ca2+ release. Biophys Soc Abstract 2183-Pos/B399.
Stauffer TP, Ahn S & Meyer T (1998). Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr Biol 8, 343–346.[CrossRef][Medline]
Suh BC & Hille B (2002). Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35, 507–520.[CrossRef][Medline]
Suh BC & Hille B (2005). Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr Opin Neurobiol 15, 370–378.[CrossRef][Medline]
Suh BC & Hille B (2006). Does diacylglycerol regulate KCNQ channels? Pflugers Arch 453, 293–301.[CrossRef][Medline]
Suh BC, Horowitz LF, Hirdes W, Mackie K & Hille B (2004). Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. J Gen Physiol 123, 663–683.
Suh BC, Inoue T, Meyer T & Hille B (2006). Rapid chemically induced changes of PtdIns(4,5),P2 gate KCNQ ion channels. Science 314, 1454–1457.
Varnai P & Balla T (1998). Visualization of phosphoinositides that bind pleckstrin homology domains: calcium and agonist-induced dynamic changes and relationship to myo-[3H] inositol-labeled phosphoinositide pools. J Cell Biol 143, 501–510.
Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE & McKinnon D (1998). KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893.
Willars GB, Nahorski SR & Challis RAJ (1998). Differential regulation of muscarinic acetylcholine receptor-sensitive polyphosphoinositide pools and consequences for signaling in human neuroblastoma cells. J Biol Chem 273, 5037–5046.
Winks JS, Hughes S, Filippov AK, Tatulian L, Abogadie FC, Brown DA & Marsh SJ (2005). Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J Neurosci 25, 3400–3413.
Yus-Najera E, Munoz A, Salvador N, Jensen BS, Rasmussen HB, Defelipe J & Villarroel A (2003). Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation. Neuroscience 120, 353–364.[CrossRef][Medline]
Zhang H, Craciun LC, Mirshahi T, Rohacs T, Lopes CM, Jin T & Logothetis DE (2003). PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37, 963–975.[CrossRef][Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. M. Klein, C. A. Ufret-Vincenty, L. Hua, and S. E. Gordon Determinants of Molecular Specificity in Phosphoinositide Regulation: PHOSPHATIDYLINOSITOL (4,5)-BISPHOSPHATE (PI(4,5)P2) IS THE ENDOGENOUS LIPID REGULATING TRPV1 J. Biol. Chem., September 19, 2008; 283(38): 26208 - 26216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Hernandez, O. Zaika, and M. S. Shapiro A Carboxy-terminal Inter-Helix Linker As the Site of Phosphatidylinositol 4,5-Bisphosphate Action on Kv7 (M-type) K+ Channels J. Gen. Physiol., August 25, 2008; 132(3): 361 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Liu, H. Liang, L. Liu, and H. Zhang Phosphatidylinositol 4,5-bisphosphate hydrolysis mediates histamine-induced KCNQ/M current inhibition Am J Physiol Cell Physiol, July 1, 2008; 295(1): C81 - C91. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. V. Quinn, P. Behe, and A. Tinker Monitoring changes in membrane phosphatidylinositol 4,5-bisphosphate in living cells using a domain from the transcription factor tubby J. Physiol., June 15, 2008; 586(12): 2855 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Mackie, L. I. Brueggemann, K. K. Henderson, A. J. Shiels, L. L. Cribbs, K. E. Scrogin, and K. L. Byron Vascular KCNQ Potassium Channels as Novel Targets for the Control of Mesenteric Artery Constriction by Vasopressin, Based on Studies in Single Cells, Pressurized Arteries, and in Vivo Measurements of Mesenteric Vascular Resistance J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 475 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Pochynyuk, V. Bugaj, A. Vandewalle, and J. D. Stockand Purinergic control of apical plasma membrane PI(4,5)P2 levels sets ENaC activity in principal cells Am J Physiol Renal Physiol, January 1, 2008; 294(1): F38 - F46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yoshida and A. Alonso Cell-Type Specific Modulation of Intrinsic Firing Properties and Subthreshold Membrane Oscillations by the M(Kv7)-Current in Neurons of the Entorhinal Cortex J Neurophysiol, November 1, 2007; 98(5): 2779 - 2794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zaika, G. P. Tolstykh, D. B. Jaffe, and M. S. Shapiro Inositol Triphosphate-Mediated Ca2+ Signals Direct Purinergic P2Y Receptor Regulation of Neuronal Ion Channels J. Neurosci., August 15, 2007; 27(33): 8914 - 8926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Robertson Regulation of ion channels and transporters by phosphatidylinositol 4,5-bisphosphate J. Physiol., August 1, 2007; 582(3): 901 - 902. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
150 ms) non-inactivating outward current with a threshold around –60 mV and half-activation at around –35 mV (from 
q, 
4, phospholipase-C 
