Permeability of the endplate membrane activated by acetylcholine to some organic cations

Maéno, Takashi; Edwards, Charles; Anraku, Mitsuo

doi:10.1002/neu.480080208

Cited by 51 publications

(37 citation statements)

References 38 publications

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“…The predominance of negatively charged residues in the putative channel entrance and exit could explain specificity for cations. The diameter of the proposed channel formed between the five A sequences arranged as parallel helices around the channel would be -7.0 A, close to the diameter found by electrophysiology (12,(31)(32)(33).…”

Section: Discussionsupporting

confidence: 83%

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Finer-Moore¹,

Stroud²

1984

Proc. Natl. Acad. Sci. U.S.A.

469

157

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Fourier analysis of the hydrophobicities of the acetylcholine receptor subunit sequences reveals regions of amphipathic secondary structure. Prediction of a consensus secondary structure based on this analysis and on an empirical prediction method leads to a testable hypothesis about how the ion channel is formed and might function. Knowledge of the three-dimensional structure of acetylcholine receptors is consistent with features of the model proposed and provides some constraints.The acetylcholine receptor (AcChoR) is an '-'250-kilodalton (kDa) complex of five homologous glycoprotein subunits in stoichiometry a2P3y8 (1)(2)(3). The four subunits each contain four hydrophobic stretches of at least 20-25 contiguous residues (4-9). The structural similarity of the five subunits and the transmembrane orientation of secondary structural features (10) imply that they surround the central ion channel like staves (11). This is the simplest arrangement that preserves quasi-equivalent interactions at the subunit interfaces. Huang et al. (12) conclude that the channel is a waterfilled pore containing hydrogen-accepting groups and at least one negatively charged site. Lewis and Stevens (13) calculated the simplest potential energy surface that can account for electrophysiological data (14). Their profile is characterized by two energy barriers separated by a shallow negative energy well, which Horn and Stevens (15) hypothesize results from one or more negatively charged sites within the channel. The dependence of conduction upon ion size for both monovalent and divalent cations has led Lewis and Stevens to conclude (i) that the ion channel environment is similar to that of free water, (ii) that the ion channel may be lined with hydrophilic residues, but (iii) that ion selectivity does not result from direct interaction of ions with amino acid side chains (16).Inspection of the y-subunit sequence for regions that might interface with a hydrophobic domain and form a hydrophilic wall of the ion channel identifies regions in which charged or very hydrophilic residues are interspersed with neutral or hydrophobic residues in a periodic fashion characteristic of regular secondary structures. This observation prompted us to quantitate the local periodicity in the hydrophobicities of the primary structures of all subunits by Fourier analysis. McLachlan has discussed Fourier analysis as a means of identifying periodic properties of amino acid sequences (17). We used Fourier analysis for amphipathic secondary structure correlation together with a secondary structure prediction method for the -75% sequence external to the bilayer and separate evidence for oriented helices in the transmembrane regions to develop an overall structural scheme. The overall predictions gain statistical significance from the congruence of all four subunit types and are consistent with the low-resolution, three-dimensional structure of AcChoR. METHODSThe premise for the analytic method is that regular secondary structural features located at an inter...

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Section: Discussionsupporting

confidence: 83%

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Finer-Moore¹,

Stroud²

1984

Proc. Natl. Acad. Sci. U.S.A.

469

157

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“…In preliminary experiments performed using 4 mM-Tris as a buffer, y for normal Na Ringer was determined to be 17-8 + 0 5 pS (n = 34). Other investigators have indicated that TRIS may be somewhat permeant through ACh channels (Ritchie & Fambrough, 1975;Steinbach, 1975;Lassignal & Martin, 1977;Maeno, Edwards & Anraku, 1977;Ascher, Marty & Neild, 1978). Still other investigators have indicated that TRIS may have adverse physiological effects on biological systems (Luthra, Ekholm, Kim & Hanahan, 1975; Gillespie & McKnight, 1976;Wilson, Clark & Pellmar, 1977).…”

Section: Single Channel Conductancementioning

confidence: 99%

Ion‐concentration dependence of the reversal potential and the single channel conductance of ion channels at the frog neuromuscular junction.

Lewis¹

1979

The Journal of Physiology

380

330

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SUMMARY1. The acetylcholine-sensitive ionic channels at the neuromuscular junction were studied in voltage-clamped single muscle fibres from a monolayer preparation of the cutaneous pectoris muscle from Rana pipiens. The experimental observations were of three types: (a) reversal potential as a function of external Na and Ca concentrations, (b) the single channel conductance (y) from noise analysis as a function of these same concentrations, and (c) y as a function of membrane potential.2. The reversal potential in normal Na Ringer was -3-8 + 0-5 mV (+ S.E. of mean, n = 22) and decreased approximately linearly as the logarithm of the outside Na activity as this activity decreased to 10 % of normal.3. The single channel conductance in normal Na Ringer was 27-5 + 0-7 pS (n = 28) and reached a limiting value close to 10 pS as Na was replaced with sucrose. 4. Increasing [Ca]. from 2 to 10 mm made the reversal potential more positive and decreased the single channel conductance. Mg caused similar effects.5. Various theories that have been used to describe the mechanism of ion permeation throuch e.p.c. channels were tested. Constant field theory (eqns. (3), (4) and (5)), a modified Takeuchi approach (eqn. (6)), and a single barrier theory (eqns. (8), (9) and (10)) could not account for all of the experimental observations. 6. In particular, constant field theory, with no assumed surface charge density, could account for the following: (a) the reversal potential measurements for solutions containing 2 mM-Ca (with PK/PN. = 1-2 and PC./PNa = 1-02), (b) the single channel conductance values for solutions containing 2 mm-Ca and Na concentrations down to 20 % of normal, (c) that y has little voltage dependence.7. However, constant field theory, with no assumed surface charge density, could not account for the following: (a) the reversal potential observed for Ringer containing 80 mM-Ca, (b) the y values observed for very low Na concentrations, (c) the observation that increasing Ca from 2 to 10 mm in a solution containing 75 % normal Na results in a decrease in y.8. From thefailure of the Takeuchi approach (eqn. (6)), it is argued that ion interactions must occur at e.p.c. channels because ion flux independence is the only assumption in the derivation of eqn. (6) without experimental verification.9. The ion interactions at e.p.c. channels probably include both surface charge effects and competition for a binding site.

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“…9Bf). It has been shown that glucosamine is a fairly impermeable cation with frog neuromuscular junctions (MAENO et al, 1977;DWYER et al, 1978).…”

Section: Camp Induced Inward Currentmentioning

confidence: 99%

Influences of pressure-injected cyclic AMP on the membrane current and characteristics of an identified neuron of Aplysia kurodai.

1985

Self Cite

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The ionic mechanism of the effect of intracellularly injected adenosine 3',5'-cyclic monophosphate (CAMP) on the membrane of identified neuron L5 of Apl ysia kurodai was investigated with conventional voltage-clamp and ion-substitution techniques. The intracellular elevation of CAMP caused an inward current ('CAMP), which was not accompanied by a significant change in membrane conductance at potentials more hyperpolarized than -60 mV. The current increased over the voltage range (-50 to -30 mV) associated with a conductance decrease and decreased at potentials more hyperpolarized than -60 mV. Elevated intracellular CAMP was found to enhance a region of negative slope resistance in steady-state I -V relations. Duration of the 'CAMP was greatly prolonged by bath-applied isobutylmethylxanthine (50 ,uM), but imidazole (10 mM) had an opposite effect on the 'CAMP. Tolbutamide (5 mM), a protein kinase inhibitor, reduced the DAMP. The current was not affected by the presence of bath-applied TTX (50 µM), ouabain (50 /LM), or triaminopyrimidine (5 mM). Reduction of [Na+]o reversibly decreased the DAMP. Li+ could largely substitute for Nat Alterations of [K+]o, and bath application of 4-AP (5 mM) and TEA (30 mM) did not affect the DAMP, In the presence of Nat, Cl-, and divalent cations such as Ca2+ and Ba2+ inhibited the DAMP. These results suggest that fast elevation of intracellular cAMP induces a TTX-resistant slow Na+ inward current, and the current might be due to activation of CAMP-dependent protein kinase.

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Permeability of the endplate membrane activated by acetylcholine to some organic cations

Cited by 51 publications

References 38 publications

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Ion‐concentration dependence of the reversal potential and the single channel conductance of ion channels at the frog neuromuscular junction.

Influences of pressure-injected cyclic AMP on the membrane current and characteristics of an identified neuron of Aplysia kurodai.

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