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Departments of 1 Physiology and 2 Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298
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ABSTRACT |
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Top
Abstract
Introduction
Results & Discussion
References
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Gadolinium (Gd3+) blocks cation-selective stretch-activated ion channels (SACs) and thereby inhibits a variety of physiological and pathophysiological processes. Gd3+ sensitivity has become a simple and widely used method for detecting the involvement of SACs, and, conversely, Gd3+ insensitivity has been used to infer that processes are not dependent on SACs. The limitations of this approach are not adequately appreciated, however. Avid binding of Gd3+ to anions commonly present in physiological salt solutions and culture media, including phosphate- and bicarbonate-buffered solutions and EGTA in intracellular solutions, often is not taken into account. Failure to detect an effect of Gd3+ in such solutions may reflect the vanishingly low concentrations of free Gd3+ rather than the lack of a role for SACs. Moreover, certain SACs are insensitive to Gd3+, and Gd3+ also blocks other ion channels. Gd3+ remains a useful tool for studying SACs, but appropriate care must be taken in experimental design and interpretation to avoid both false negative and false positive conclusions.
mechanosensitive channels; mechanoelectrical feedback; lanthanides; chelation
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INTRODUCTION |
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Top
Abstract
Introduction
Results & Discussion
References
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THE IDENTIFICATION OF stretch-activated channels (SACs) in bacteria, plant, and animal cells has led to intense efforts to elucidate their physiological and pathophysiological roles (9, 27, 32). SACs are implicated in a wide range of responses to mechanical perturbations, including cell volume regulation, increased intracellular Ca2+, cell proliferation, gene expression, DNA synthesis, baroreceptor discharge, altered cardiac electrical activity, and release of atrial natriuretic factor (for review, see Ref. 9).
Gadolinium (Gd3+), a trivalent lanthanide, has emerged as the most commonly used tool to identify phenomena dependent on SACs (9). Millet and Pickard (25) originally postulated that Gd3+ blocks mechanosensitive ion channels on the basis of its ability to inhibit orientation of the roots of pea plants (Zea mays) in response to surface contact, thigmotropism, and gravity, geotropism. Direct evidence was provided by Yang and Sachs (41) who showed that Gd3+ blocks stretch-activated cation channels in Xenopus laevis oocytes. Often, 10 µM Gd3+ is sufficient to largely block cation SACs and thereby inhibit mechanosensitive processes (9, 27, 32). By extension, the inability of Gd3+ to modulate certain stretch-dependent events has been taken to imply that SACs are not involved.
The purpose of this communication is to highlight several methodological concerns. A review of recent literature indicates that Gd3+ sometimes is applied in the presence of anions that avidly bind free Gd3+ and effectively remove it from the experimental solution (4, 11, 13-16, 20-23, 29, 31, 33, 40). Notable among these anions are phosphate, carbonate, EGTA, sulfate, carboxylic acids, and albumin, which often are contained in physiological salt solutions and culture media. The use of Gd3+ with anions that avidly bind it can lead to false negative conclusions regarding the role of SACs in physiological processes. False negatives also can arise because several SACs are not blocked by Gd3+ (34, 41). On the other hand, false positives can arise because Gd3+ is not very specific (9).
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RESULTS AND DISCUSSION |
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Top
Abstract
Introduction
Results & Discussion
References
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Binding of
Gd3+.
Martell and Smith (24) and Evans (7) have provided critically reviewed
stability constants for the interaction of
Gd3+ with a number of inorganic
anions, carboxylic acids, and amine polycarboxylic acid chelators
(e.g., EGTA). Selected constants are listed in Table
1. For example, the equilibrium dissociation constants
for PO3
4 and
CO23 are given as
1022.3 and
1032.2, respectively. These
values indicate that physiological anions are high-affinity ligands for
Gd3+.
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4 and
CO23, but rather are present as
protonated species.
To calculate the free Gd3+
concentration, the distribution of anionic species first was calculated
from the apparent acidic dissociation constant
(pKa) values
and solubility of CO2
(Q'CO2) at an ionic strength of 0.16 M and 25°C, assuming the experimental solutions contained either 1 mM total inorganic phosphate or were equilibrated with 5% CO2. For
carbonates, the adopted
pKa values were
6.22 and 9.94 (30), and
Q'CO2
was taken as 0.0331 mM/mmHg (5). Gassing with 5%
CO2 gives a
PCO2 of
36.8 mmHg in the face of a water vapor pressure of 23.8 mmHg (39). For phosphates, the
pKa values were
2.02, 6.81, and 11.68 (30). The interaction of
HPO24 and
Na+ was accounted for by using a
dissociation constant of
100.6 (24) and assuming
Na+ in the experimental solutions
was 130 mM. The dissociation constant for
K+,
100.49 (24), is similar to
that of Na+, and for present purposes,
K+ was not considered separately.
Although the calculated concentrations of
PO34 and
CO23 at pH 7.4 are very low under
these conditions, 2.96 × 108 and 5.3 × 105 M, respectively, the
large excess of phosphates and carbonates with respect to
Gd3+ assures that mass action will
maintain PO34 and
CO23 virtually constant as the
unprotonated species bind to Gd3+.
With PO34 and
CO23 known, the free
Gd3+ concentration was directly
calculated for 10 µM total Gd3+
from the equilibrium constant (Table 1). The calculations indicate that
free Gd3+ is only ~2 × 1020 M in the presence of
phosphate and ~6 × 1013 M in the presence of a
bicarbonate buffer system. For simplicity, the
Gd3+ dissociation constants in
Martell and Smith (24) were not corrected for ionic strength. Moreover,
~10% of free Gd3+ was in the
form GdOH2+ due to hydrolysis
(30). Thus these calculations should be regarded as order of magnitude
estimates only. Nevertheless, the calculated values are sufficiently
accurate to show that the free
Gd3+ concentration is vanishingly
low in the presence of certain physiological anions. Therefore, failure
to detect an effect of Gd3+ in
phosphate- or bicarbonate-buffered solutions does not by itself provide
credible evidence regarding the role of SACs.
Several studies on Ca2+ currents
and muscle contraction previously led to the qualitative conclusion
that phosphate and bicarbonate buffer systems interfered with the
action of Gd3+ (3, 19, 38) and
reduced the potency of Gd3+ as a
blocker of SACs (9). However, the extent of the interaction between
Gd3+ and these anions apparently
was not fully appreciated, and calculations of the free
Gd3+ concentration from
equilibrium constants in the literature were not made.
Available evidence suggests that HEPES, PIPES, MOPS, and imidiazole are
appropriate buffers for use with lanthanides because the affinity of
lanthanides for organic sulfate groups and nitrogen donors is very weak
(7). On the other hand, both TES and Tris interact with lanthanides to
some extent, and phosphate and bicarbonate systems should be
strenuously avoided.
Although the present discussion has focused on phosphate and
bicarbonate, the equilibrium constant for EGTA (Table 1) indicates that
it also should not be included in solutions designed to evaluate the
effect of Gd3+. Failure to
recognize this interaction may confound aspects of the interpretation
of several recent studies (14-16, 23, 31). The consequence of
inclusion of anions that bind Gd3+
with lower affinity is less clear, and case-by-case calculations of
free Gd3+ concentration are
necessary.
The concern that binding of Gd3+
to anions can lead to false negative conclusions is based on the
premise that free Gd3+ is the
species responsible for blocking SACs. This presumption has not been
evaluated in detail, and the possibility that certain Gd3+-anion complexes can block
SACs and other ion channels cannot be rigorously excluded. Such an
interaction may in part explain several studies reporting effects of
Gd3+ in the presence of phosphate
and bicarbonate (10, 12, 35, 36).
Other sources of error. False negative conclusions also can arise because some SACs have been shown to be insensitive to Gd3+ in studies conducted in the absence of anions with high affinity for this lanthanide. Among the Gd3+-insensitive SACs are K+-selective SACs in rat astrocytes (41) and snail (Lymnaea) neurons (34).
A final concern in using Gd3+ as a marker for SACs is that false positive findings may emerge because Gd3+ is not a specific antagonist. Besides SACs, Gd3+ can block L-type (1, 17, 18, 33), T-type (1, 26), and N-type Ca2+ (2, 3), Na+(6), K+ (6, 12), and Ca2+-activated Cl (37) channels, as well
as purine P2X channels (28) and muscarinic receptor-mediated
Ca2+ transients (8), at
concentrations that may overlap those used to block SACs. Thus it is
essential to confirm a positive response to
Gd3+ with other experimental
paradigms before concluding that SACs are responsible for the process
under study.
As in all methods, the use of Gd3+
to identify processes that involve SACs has limitations. In this case,
the limitations include the chemical interactions of
Gd3+ with physiological anions,
its imperfect selectivity, and the presence of
Gd3+-insensitive SACs in some
preparations. Recognition of these limitations allows the
experimentalist to draw correct inferences.
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ACKNOWLEDGEMENTS |
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We thank Dr. Joseph J. Feher for comments on the manuscript.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-46764 and HL-02798.
Address for reprint requests: C. M. Baumgarten, Dept. of Physiology, Medical College of Virginia, Richmond, VA 23298-0551.
Received 19 November 1997; accepted in final form 29 April 1998.
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Top
Abstract
Introduction
Results & Discussion
References
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G.-R. Li and C. M. Baumgarten Modulation of cardiac Na+ current by gadolinium, a blocker of stretch-induced arrhythmias Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H272 - H279. [Abstract] [Full Text] [PDF]
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 X. Su, R. E. Wachtel, and G. F. Gebhart Mechanosensitive Potassium Channels in Rat Colon Sensory Neurons J Neurophysiol, August 1, 2000; 84(2): 836 - 843. [Abstract] [Full Text] [PDF]
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 R. M. Roman, A. P. Feranchak, A. K. Davison, E. M. Schwiebert, and J. G. Fitz Evidence for Gd3+ inhibition of membrane ATP permeability and purinergic signaling Am J Physiol Gastrointest Liver Physiol, December 1, 1999; 277(6): G1222 - G1230. [Abstract] [Full Text] [PDF]
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C. M. Waters, K. M. Ridge, G. Sunio, K. Venetsanou, and J. I. Sznajder Mechanical stretching of alveolar epithelial cells increases Na+-K+-ATPase activity J Appl Physiol, August 1, 1999; 87(2): 715 - 721. [Abstract] [Full Text] [PDF]
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E. Carmeliet Cardiac Ionic Currents and Acute Ischemia: From Channels to Arrhythmias Physiol Rev, July 1, 1999; 79(3): 917 - 1017. [Abstract] [Full Text] [PDF]
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 C. R. Halaszovich, C. Zitt, E. Jungling, and A. Luckhoff Inhibition of TRP3 Channels by Lanthanides. BLOCK FROM THE CYTOSOLIC SIDE OF THE PLASMA MEMBRANE J. Biol. Chem., November 22, 2000; 275(48): 37423 - 37428. [Abstract] [Full Text] [PDF]
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 A. F. Antoine, J.-E. Faure, S. Cordeiro, C. Dumas, M. Rougier, and J. A. Feijo A calcium influx is triggered and propagates in the zygote as a wavefront during in vitro fertilization of flowering plants PNAS, September 12, 2000; 97(19): 10643 - 10648. [Abstract] [Full Text] [PDF]
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F. Boudreault and R. Grygorczyk Cell swelling-induced ATP release and gadolinium-sensitive channels Am J Physiol Cell Physiol, January 1, 2002; 282(1): C219 - C226. [Abstract] [Full Text] [PDF]
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R. R. Lamberts, M. H. P. van Rijen, P. Sipkema, P. Fransen, S. U. Sys, and N. Westerhof Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1334 - H1340. [Abstract] [Full Text] [PDF]
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