Monovalent cation (MC) current in cardiac and smooth muscle cells: regulation by intracellular Mg<sup>2+</sup> and inhibition by polycations

Zakharov, Sergey I.; Smani, Tarik; Leno, Endri; Mačianskienė, Regina; Mubagwa, Kanigula; Bolotina, Victoria M.

doi:10.1038/sj.bjp.0705074

Cited by 20 publications

(39 citation statements)

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“…We previously showed (10,31,48) that I MIC in cardiac myocytes is unmasked on cell dialysis with low internal Mg 2ϩ and that the channel is permeable to divalent and monovalent cations. Unless stated otherwise, the data presented are from pig cells.…”

Section: Resultsmentioning

confidence: 99%

“…We previously described (10,31,48) a Mg 2ϩ -inhibited cation (MIC) channel in cardiac myocytes that displays pharmacological and pore properties resembling those of TRPM6 and TRPM7 channels. Native TRPM7-like currents such as cardiac MIC are also referred to as magnesium-nucleotideregulated metal ion (MagNuM) currents (32).…”

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“…8,34). Like TRPM6 and TRPM7 channels, cardiac and smooth muscle MIC channels are mainly regulated by cytosolic Mg 2ϩ (48), but the slow increase of whole cell MIC current (I MIC ) on cell dialysis with low-Mg 2ϩ solution suggests that other factors apart from a simple washout of intracellular Mg 2ϩ (35) are involved. We observed (10) that in ATP-depleted cells I MIC was not sustained but decreased with time until complete loss.…”

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ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

Gwanyanya¹,

Sipido²,

Vereecke³

et al. 2006

American Journal of Physiology-Cell Physiology

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The Mg 2ϩ -inhibited cation (MIC) current (I MIC) in cardiac myocytes biophysically resembles currents of heterologously expressed transient receptor potential (TRP) channels, particularly TRPM6 and TRPM7, known to be important in Mg 2ϩ homeostasis. To understand the regulation of MIC channels in cardiac cells, we used the whole cell voltage-clamp technique to investigate the role of intracellular ATP in pig, rat, and guinea pig isolated ventricular myocytes. I MIC, studied in the presence or absence of extracellular divalent cations, was sustained for Ն50 min after patch rupture in ATP-dialyzed cells, whereas in ATPdepleted cells I MIC exhibited complete rundown. Equimolar substitution of internal ATP by its nonhydrolyzable analog adenosine 5Ј-(␤,␥-imido)triphosphate failed to prevent rundown. In ATP-depleted cells, inhibition of lipid phosphatases by fluoride ϩ vanadate ϩ pyrophosphate prevented I MIC rundown. In contrast, under similar conditions neither the inhibition of protein phosphatases 1, 2A, 2B or of protein tyrosine phosphatase nor the activation of protein kinase A (forskolin, 20 M) or protein kinase C (phorbol myristate acetate, 100 nM) could prevent rundown. In ATP-loaded cells, depletion of phosphatidylinositol 4,5-bisphosphate (PIP 2) by prevention of its resynthesis (10 M wortmannin or 15 M phenylarsine oxide) induced rundown of I MIC. Finally, loading ATP-depleted cells with exogenous PIP 2 (10 M) prevented rundown. These results suggest that PIP 2, likely generated by ATP-utilizing lipid kinases, is necessary for maintaining cardiac MIC channel activity. cation channels; hydrolysis; phosphoinositides; rundown SEVERAL ION CHANNELS PARTICIPATE in ion fluxes that are critical for cardiac function. Apart from the well-characterized cationselective voltage-gated, ligand-gated, and background ion channels as well as the pacemaker channels, the nature of other cardiac cation-permeable channels remains unclear. In cardiac and other tissues, transient receptor potential (TRP) proteins are molecular candidates for cation-permeable channels (36). The TRP proteins are members of three main (TRPC, TRPV, and TRPM) and some more distantly related subfamilies. They form channels gated by stimuli such as voltage, chemical, or physical factors and are involved in both physiological and pathological functions (36).We previously described (10, 31, 48) a Mg 2ϩ -inhibited cation (MIC) channel in cardiac myocytes that displays pharmacological and pore properties resembling those of TRPM6 and TRPM7 channels. Native TRPM7-like currents such as cardiac MIC are also referred to as magnesium-nucleotideregulated metal ion (MagNuM) currents (32). TRPM6 and TRPM7 are closely related members of the TRPM subfamily, which form channels with very similar properties (29, 45). TRPM6 is mainly expressed in the kidney and small intestines, and its mutation causes hypomagnesemia with secondary hypocalcemia (5, 41, 46). TRPM7 is widely expressed with high levels in the kidney and heart. It is essential for cell viability and prolife...

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Section: Resultsmentioning

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ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

Gwanyanya¹,

Sipido²,

Vereecke³

et al. 2006

American Journal of Physiology-Cell Physiology

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“…In RBL and Jurkat T cells, the native correlate of TRPM7 was described and termed MagNuM (magnesium nucleotide-dependent metal cation) (14), or MIC (Mg 2ϩ -inhibited cation) (15,16). Similar currents have also been described in cardiac fibroblasts (17), smooth muscle cells (18), and brain microglia (19). The role of the kinase domain and phosphorylation in the ion channel function is controversial (for a recent review, see Ref.…”

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Channel Function Is Dissociated from the Intrinsic Kinase Activity and Autophosphorylation of TRPM7/ChaK1

Matsushita

Kozak

Shimizu³

et al. 2005

Journal of Biological Chemistry

178

213

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TRPM7/ChaK1 is a unique channel/kinase that contains a TRPM channel domain with 6 transmembrane segments fused to a novel serine-threonine kinase domain at its C terminus. The goal of this study was to investigate a possible role of kinase activity and autophosphorylation in regulation of channel activity of TRPM7/ChaK1. Residues essential for kinase activity were identified by site-directed mutagenesis. Two major sites of autophosphorylation were identified in vitro by mass spectrometry at Ser 1511 and Ser 1567 , and these sites were found to be phosphorylated in intact cells. TRPM7/ ChaK1 is a cation-selective channel that exhibits strong outward rectification and inhibition by millimolar levels of internal [Mg 2؉ ]. Mutation of the two autophosphorylation sites or of a key catalytic site that abolished kinase activity did not alter channel activity measured by whole-cell recording or Ca 2؉ influx. Inhibition by internal Mg 2؉ was also unaffected in the autophosphorylation site or "kinase-dead" mutants. Moreover, kinase activity was enhanced by Mg 2؉ , was decreased by Zn 2؉ , and was unaffected by Ca 2؉ . In contrast, channel activity was inhibited by all three of these divalent cations. However, deletion of much of C-terminal kinase domain resulted in expression of an apparently inactive channel. We conclude that neither current activity nor regulation by internal Mg 2؉ is affected by kinase activity or autophosphorylation but that the kinase domain may play a structural role in channel assembly or subcellular localization.Recent studies have characterized several unique protein kinases that display no amino acid sequence similarity to the superfamily of protein kinase A-related enzymes, including eukaryotic elongation factor-2 kinase (EF2K) 1 and Dictyostelium myosin heavy chain kinases A, B, and C (MHCK A-C). Several additional catalytic domains related to EF2K and MHCK have been identified through data base searches in mammals as well as in nematode worm, although the function of these potential protein kinases is not known (1-3). Using this approach, we and others identified an 1863-amino acid polypeptide (termed ChaK for channel kinase) that contained a TRP-related channel domain fused to the atypical kinase domain at its C terminus (3, 4). The same gene product was also identified in a yeast two-hybrid screen using a portion of phospholipase C ␤1 as bait (and termed TRP-PLIK) (5) and in a screen for TRP-related channels (and termed LTRPC7) (6). Based on revised nomenclature for TRP channels, the kinasecontaining TRP has been termed TRPM7/ChaK1 based on its similarity to long TRP family members, melastatin, MTR1 (TRPM5), and LTRPC2 (TRPM2) (7). A closely related gene, TRPM6/ChaK2 has also been identified as being mutated in familial hypomagnesemia (8, 9), and a key role for both TRPM6 and TRPM7 has been suggested in Mg 2ϩ homeostasis (8 -11).Members of the TRP family of channels contain six predicted transmembrane segments and are related to the superfamily of ion channels that include voltage-gated K ϩ...

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“…These interactions include the block of inwardly rectifying K þ channels (Lopatin et al, 1994), cyclic nucleotide-gated channels (Lu & Ding, 1999;Guo & Lu, 2000), glutamate-activated receptor channels (Araneda et al, 1999), nicotinic acetylcholine receptor channels (Haghighi & Cooper, 1998), sodium channels (Huang & Moczydlowski, 2001) and voltage-gated calcium channels (Gomez & Hellstrand, 1995;. Many types of monovalent cation selective channels are also blocked by extracellular polycations like spermine in the mM range (Nilius, 2003;Zakharov et al, 2003). The molecular nature of channels carrying mI CAT is not yet completely defined, but they appear to be homo-or heteromultimers of transient receptor potential proteins (Lee et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Effects of polyamines on the muscarinic receptor-operated cation current in guinea-pig ileal smooth muscle myocytes

Tsvilovskyy

Zholos

Bolton

2004

British Journal of Pharmacology

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1 The effects of extracellular and intracellular polyamines (PAs), spermine and putrescine, on the cation current (mI CAT ) evoked either by activating muscarinic receptors with carbachol or by intracellularly applied GTPgS (in the absence of carbachol) were studied using patch-clamp recording techniques in single guinea-pig ileal myocytes. 2 Extracellular spermine and putrescine rapidly and reversibly inhibited mI CAT in a concentrationand voltage-dependent manner with the IC 50 values at À40 mV of about 1 and 5 mM, respectively. Membrane depolarization relieved the blocking action of PAs although cation conductance activation curve remained N-shaped. The inhibition was similar for both carbachol-and GTPgS-evoked currents, suggesting that the cation channel rather than the muscarinic receptor was the primary site of the PA action. In outside-out membrane patches, both cation channel unitary conductance and open probability were reduced. 3 In perforated-patch experiments used to retain cytoplasmic PAs sustained 100 mM carbacholinduced mI CAT was significantly smaller (478776 pA, n ¼ 7) compared to that recorded using conventional whole-cell configuration with nominally PA-free pipette solution (1314776 pA, n ¼ 12), but comparable in size to mI CAT with 0.3 mM spermine in the pipette solution (509741 pA, n ¼ 19). Intracellular putrescine inhibited mI CAT less potently compared to spermine. 4 In conclusion, these results show a novel role of intestinal PAs in mI CAT inhibition, which can contribute to their well-known suppressing effect on the gastrointestinal smooth muscle excitability and contractility.

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Monovalent cation (MC) current in cardiac and smooth muscle cells: regulation by intracellular Mg²⁺ and inhibition by polycations

Cited by 20 publications

References 50 publications

ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

Channel Function Is Dissociated from the Intrinsic Kinase Activity and Autophosphorylation of TRPM7/ChaK1

Effects of polyamines on the muscarinic receptor-operated cation current in guinea-pig ileal smooth muscle myocytes

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Monovalent cation (MC) current in cardiac and smooth muscle cells: regulation by intracellular Mg2+ and inhibition by polycations

Cited by 20 publications

References 50 publications

ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

Channel Function Is Dissociated from the Intrinsic Kinase Activity and Autophosphorylation of TRPM7/ChaK1

Effects of polyamines on the muscarinic receptor-operated cation current in guinea-pig ileal smooth muscle myocytes

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Monovalent cation (MC) current in cardiac and smooth muscle cells: regulation by intracellular Mg²⁺ and inhibition by polycations

ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

ATP and PIP₂ dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes