Function of nicotinic acetylcholine receptors.

In summary, the AChRs on BC3H-1 cells behave in a fashion consistent with the major properties expected of muscle nicotinic AChRs. The results we have discussed here provide a quantitative description of some of the steps in receptor activation, and give a general picture of the functional states the AChR adopts. The results provide a framework for biochemical and ultrastructural studies of the AChR as well. One clear problem is that the receptor with an open channel is a very low probability state at equilibrium, at any concentration. A second problem is the postulated existence of closed channel states associated with brief-duration openings. It is not known what the probability is that a receptor is in such a state, so even "resting" receptors at low agonist concentrations may be in several functional states. At high agonist concentrations the receptor population goes through several transient states before reaching the final equilibrium state. At 11 degrees C, with a high concentration of ACh (greater than 0.3 mM) receptors with open channels appear rapidly (rate approximately 500 sec-1). Initially, there is a high probability that a receptor is both doubly liganded and has an open channel (0.9, Fig. 6). However, the predesensitized state develops rapidly (approximately 30 sec-1), and eventually the probability reaches about 0.4 that doubly liganded receptors are predesensitized. The short-lived desensitized state develops at a rate of about 3 sec-1. After a second or so, the distribution is about 0.3:0.2:0.5 for AChRs between receptors with open channels, predesensitized receptors, and short-lived desensitized receptors. Long-lived desensitization develops at a rate of about 0.5 sec-1, but at equilibrium the probability that a receptor is in this state is above 0.99. For AChRs on BC3H-1 cells, and most likely all AChRs, biochemical and structural studies need to be made in a narrow time window to catch an appreciable fraction of the receptors in any of the transient functional states described. Only time-resolved biochemical studies will provide the structural information necessary to work out the relationship between structure and function for the ACh receptor and give some substance to the ghostly kinetic states necessary to describe channel function.