Function of Mammalian Nicotinic Acetylcholine Receptors

Steinbach, Joe Henry; Covarrubias, Manuel; Sine, Steven M.; Steele, Joy A.

doi:10.1007/978-3-642-71649-2_17

Cited by 10 publications

(9 citation statements)

References 24 publications

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“…Weiland & Taylor (1979) reported no change in the affinity of agonists for Torpedo receptor after exposure to DMT. Sine & Taylor (1979) (Steinbach, 1980;Sakmann, Patlak & Neher, 1980 (Colquhoun & Sakmann, 1981;Takeda & ,Trautmann, 1984). The present results show that DMT does not activate receptor channels when only the high-affinity site is occupied, but triggers both brief-and long-duration openings when both sites are occupied.…”

Section: High-resolution Measurements Of Channel-open Durationsmentioning

confidence: 53%

Acetylcholine receptor activation by a site‐selective ligand: nature of brief open and closed states in BC3H‐1 cells.

Sine¹,

Steinbach

1986

The Journal of Physiology

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SUMMARY1. Single-channel currents were recorded through acetylcholine receptor channels of clonal BC3H-1 muscle cells activated by the curare-like compound, (+ )-dimethyltubocurarine (DMT).2. DMT binds selectively to the two a-neurotoxin-binding sites on these receptors, with apparent dissociation constants differing by about 100-fold (Sine & Taylor, 1981). Receptor channels do not open with DMT bound only to the high-affinity site, but only at DMT concentrations at which both high-and low-affinity sites are occupied.3. Open-duration histograms are not single exponential, but are described by the sums of two (or three) exponentials. Both brief-and long-duration openings are observed in the presence of 3 /LM-DMT, and are seen at the same relative frequency up to 80 JSM-DMT. 6. It is concluded that both brief-and long-duration openings arise from receptors with two molecules of DMT bound. Furthermore, brief closures in general do not appear to reflect receptor activation processes. Instead, they seem to arise through entry to a closed state with properties independent of the agonist, but characteristic of open channels.

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Section: High-resolution Measurements Of Channel-open Durationsmentioning

confidence: 53%

Acetylcholine receptor activation by a site‐selective ligand: nature of brief open and closed states in BC3H‐1 cells.

Sine¹,

Steinbach

1986

The Journal of Physiology

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“…Magleby & Stevens S. M. SINE AND J. H. STEINBACH (1972) suggested a scheme in which the binding of agonist is rapid and at equilibrium, whereas changes in channel conformation are slower, with an opening rate, fi, and closing rate, a. In the past decade, experiments have supported expanded versions of this two-step scheme, and transition rate estimates have been obtained for reaction steps within these schemes (Steinbach, 1980;Adams, 1981). However, the precise mechanism of receptor activation remains elusive, and it is still debated whether receptor activation is limited by agonist binding steps or by channel conformational changes.…”

Section: Introductionmentioning

confidence: 89%

Activation of acetylcholine receptors on clonal mammalian BC3H‐1 cells by low concentrations of agonist.

Sine¹,

Steinbach²

1986

The Journal of Physiology

126

139

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SUMMARY1. The patch-clamp technique was used to examine the activation of single acetylcholine receptor channels of clonal BC3H-1 mouse muscle cells. Single-channel currents were activated by low concentrations of the strong agonists acetylcholine (ACh, 50-100 nM), carbamyleholine (1-2 /iM), and suberyldicholine (30-50 nM).2. At low agonist concentrations channel openings occur as isolated short-duration openings and as bursts of longer duration openings separated by brief closed periods.3. Two distinct types of brief closed periods separate long duration openings: brief closures (mean duration, 50 Its) and intermediate closures (mean duration, 05-1 0 ms).4. The kinetic properties ofintermediate closures depend on the agonist, suggesting that they reflect receptor reopening from the closed state leading to the open state. Properties of brief closures, in contrast, are independent of the agonist, indicating that they result from an additional closed state leading away from the pathway producing the open state.5. A receptor activation scheme is proposed which accounts for the observed closed states, and transition rate estimates are presented for steps within the proposed scheme.6. The channel opening rate, /1, differs several-fold for the agonists studied (200-1400 s-') and is comparable to the dissociation rate, k12 (900 s1). The dissociation rate is similar for the three agonists studied. The channel closing rate, a, is much slower than the opening rate (20-60 s'1). The probability is high that a doubly liganded channel is in the open state and depends on the agonist (0 75-0 97). 7. ,1 increases and a decreases at more negative membrane potentials, whereas k-2 shows little potential dependence.

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“…Agonists bound at the orthosteric site of nAChRs initially stabilize the open state and later a desensitized closed state, while effectors bound at the allosteric site can modify the energy barriers between transitions that shifts the equilibrium between states (Bertrand and Gopalakrishnan, 2007). Desensitization state may encompass short-and long-lived states of desensitization where the latter state is favored by long exposure to low concentration of agonists (Steinbach and Sine, 1987;De Biasi and Dani, 2011). Electrophysiology has been pivotal in determining the biophysical and pharmacological properties of different nAChRs subtypes.…”

Section: Pharmacology Of Nachrsmentioning

confidence: 99%

Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

Abraham

Lewis

2020

Front. Neurosci.

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Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

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Function of Mammalian Nicotinic Acetylcholine Receptors

Cited by 10 publications

References 24 publications

Acetylcholine receptor activation by a site‐selective ligand: nature of brief open and closed states in BC3H‐1 cells.

Acetylcholine receptor activation by a site‐selective ligand: nature of brief open and closed states in BC3H‐1 cells.

Activation of acetylcholine receptors on clonal mammalian BC3H‐1 cells by low concentrations of agonist.

Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

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