Numerical reconstruction of the quantal event at nicotinic synapses

Abstract

To test our present quantitative knowledge of nicotinic transmission, we reconstruct the postsynaptic conductance change that results after a presynaptic nerve terminal liberates a quantum of acetylcholine (ACh) into the synaptic cleft. The theory assumes that ACh appears suddenly in the cleft and that is subsequent fate is determined by radial diffusion, by enzymatic hydrolysis, and by binding to receptors. Each receptor has one channel and two ACh binding sites; the channel opens when both sites are occupied and the rate-limiting step id the binding and dissociation of the second ACh molecule. The calculations reproduce the experimentally measured growth phase (200 microseconds), peak number of open channels (2,000), and exponential decay phase. The time constant of the decay phase exceeds the channel duration by approximately equal to 20%. The normal event is highly localized: at the peak, two-thirds of the open channels are within an area of 0.15 micrometer 2. This represents 75% of the available channels within this area. The model also simulates voltage and temperature dependence and effects of inactivating esterase and receptors. The calculations show that in the absence of esterase, transmitter is buffered by binding to receptors and the postsynaptic response can be potentiated.

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

“…This prediction was borne out by their experimental results, using a-bungarotoxin to reduce the effective concentration of ACh receptors (Land et al 1981). In addition, both Land et al (1984) and Wathey et al (1979) (Sakmann, 1978;Jackson, Wong, Morris, Lecar & Christian, 1983 …”

“…Of the many models that have been proposed to simulate synaptic currents (Magleby & Stevens, 1972a;Gage, 1976;Steinbach & Stevens, 1976;Rosenberry, 1979;Wathey, Nass & Lester, 1979;Land, Salpeter & Salpeter, 1980, 1981Land, Harris, Salpeter & Salpeter, 1984;Madsen, Edeson, Lamtt & Milne, 1984;Madsen, Edeson & Milne, 1987), those presented by Land et al (1981Land et al ( , 1984 and Wathey et al (1979) are of particular relevance to the present work, since, in these models, receptor density was one of the parameters explicitly examined. Thus, for example, Land et al (1981) concluded that, when the esterase is blocked, no correlation between miniature endplate current (MEPC) amplitude and rise time is to be expected if receptor density is high, while a positive correlation is anticipated if the density is reduced.…”

Proteoglycans: Master regulators of molecular encounter?

“…The cell has only a brief interval in which to "capture" the growth factor, and this will depend exquisitely on the kinetics of growth factorreceptor binding. If this interval is followed by another "pulse" of growth factor, and then another, one can develop a model system in which kinetics, rather than affinity, plays the predominant role in determining timeaveraged receptor occupancy (related models have been used to describe neurotransmission at synapses [Wathey et al, 1979]). It is not known whether growth factors are released in such a pulsatile fashion, but with heparin-binding growth factors, it is likely that binding to the extracellular matrix would accelerate the removal of growth factor from solution, effectively narrowing the duration of any pulse and further enhancing the dependence of binding on kinetic, rather than thermodynamic, parameters.…”

Regulation by exercise of the pool of G4 acetylcholinesterase characterizing fast muscles: opposite effect of running training in antagonist muscles

“…In contrast, the cojunctional compartment of G,, in particular the membranebound and secreted G, molecules concentrated around the endplates, occupy a perfect strategic position in order to very effectively remove ACh molecules diffusing away from the postsynaptic membrane (Gisiger andStephens, 1982-1983). The available data suggest that, whereas only little of the transmitter released by a single quanta1 event is able to leave the synaptic cleft (still up to 20%, according to Wathey et al, 1979; see also Rotundo and Fambrough, 1986), the amount of ACh escaping AChE molecules immobilized on junctional structures is actually far from negligible during muscle activation. Indeed, in vivo muscle stimulation is delivered in trains of rapidly succeeding impulses and an effective stimulus corresponds to a pulse of 1O-4 M ACh over a background level of about 1O-8 M (for review, see Changeux, 1981).…”