| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Nicotinic receptors and P2X ATP receptors both incorporate transmembrane cation channels as part of the receptor moiety. However, the nicotinic and P2X ATP receptors are regarded as entirely independent molecular entities and the receptor subunits have distinctly different transmembrane topologies. Given this difference, it is of interest that recent papers (Searl et al. 1998; and two papers appearing in this issue of The Journal of Physiology: Zhou & Galligan, 1998; Barajas-Lopez et al. 1998) have confirmed earlier findings (Nakazawa et al. 1991; Silinsky & Gerzanich, 1993) that co-application of nicotinic agonists and P2X ATP receptor agonists produce less than the additive responses predicted by independent receptor activation. These papers, when taken together, suggest that such interdependent, mutually occlusive interactions are: (i) receptor mediated (as antagonists reveal full responses of the unaffected agonist); (ii) not mediated by soluble second messengers (as non-additivity is also seen in excised patches); and (iii) not due to pH changes produced by high concentrations of agonist (Wildman et al. 1997).
Figure 1 depicts three mechanisms that could account for non-additive responses to nicotinic and ATP receptor agonists. In A, both receptors are intimately linked, such that the binding of agonist to one type of receptor inhibits the opening of the other. In B, both receptors are closely associated and inward cationic current through one receptor inhibits the opening of the other. In C, the receptors are independent but each receptor contains an inhibitory binding site for the other receptor agonist.
Several experiments should distinguish between these models. The work of Barajas-López et al. (1998), performed using saturating concentrations of agonists, suggests that inward current through one class of receptor acts locally to inhibit the activation of the other receptor class, whilst outward currents are merely additive (Fig. 1B). If this model is true, then selective nicotinic channel blockers, such as procaine, known not to bind to the agonist recognition site, should reverse the occlusion of the ATP-receptor channel. Possibly, mere occupation of a strategic site in the channel by cations entering from the outside occludes the gating of the other channel. Intriguingly, the P2X ATP receptor in guinea-pig ganglia exhibits profound inward rectification (see Silinsky & Gerzanich, 1993), as may the nicotinic receptor in some instances. Models using ion channels constructed from artificial peptides suggest that inward rectification can be attributed to a dipole potential produced by parallel peptide helices in the pore-forming region of the channel (see e.g. Kienker et al. 1994). Perhaps a permeant ion entering from the outside can interact with such a dipole potential, maybe in conjunction with fixed charges, and influence the gating properties and the conductance of its own channel and that of a closely associated receptor. In this regard, Zhou & Galligan (1998), also using saturating concentrations of agonists, found that when agonists at GABAA and 5-HT3 receptors (receptors that do not exhibit inward rectification of the single channel conductance in guinea-pig autonomic neurons) were combined with ACh or ATP, additivity of responses occurred. In may also be that these other receptors are not as intimately positioned as the nicotinic and P2X ATP receptors in these preparations. In contrast, Nakazawa et al. (1995) and Searl et al. (1998) have found that inhibition can occur using concentrations of the occluding agonist that produce by themselves little to no inward currents. Nakazawa et al. (1995) reported that ATP (100 fM) occluded responses of recombinant ganglionic nicotinic receptors in Xenopus oocytes. This latter finding suggests that the model in Fig. 1C could be correct in some instances. Outside-out patches containing only one receptor class could be examined to test this.
 |
View larger version [in this window] [in a new window] |
|
|
As depicted, mechanisms A-C represent decreasing membrane intimacy between the two types of receptors. In A, the receptors are closely associated and the opening of one receptor inhibits the opening of the other. Whilst the model is depicted as separate channels, it is also possible that both types of receptors are arranged around a common pore (see e.g. Nakazawa et al. 1991). In B, inward current through one receptor inhibits either the opening or the passage of current through the other nearby receptor. In C, the receptors are not in close proximity but the ATP receptor contains an inhibitory nicotinic binding site and/or the nicotinic receptor contains an inhibitory ATP binding site. For the sake of simplicity, in models A and B we show activation of the nicotinic channels occluding the ATP response. The converse may be equally true, however. | ||
At present our understanding of the mechanisms by which nicotinic and P2X ATP receptor agonists could interact is hampered by our lack of knowledge about P2X receptors, e.g. whilst nicotinic receptors contain nicotinic and ATP binding sites, the ATP binding site on P2X receptors is still equivocal. It will be interesting to see whether interactions occur using cloned neuronal nicotinic receptors expressed in HEK cells (which appear to closely resemble the intact ganglion; Sivilotti et al. 1997) and cloned human P2X3 ATP receptors (whose agonist selectivity sequence resembles those of some ganglionic P2X receptors; see Silinsky & Gerzanich, 1993).
| Barajas-López, C., Espinosa-Luna R. & Zhu, Y. (1998). The Journal of Physiology 513, 671-683 | [Abstract/Full Text] |
| Kienker, P. K., Degrado, W. F. & Lear, J. D. (1994). Proceedings of the National Academy of Sciences of the USA 91, 4859-4863 | [Abstract] |
| Nakazawa, K., Fujimori, K., Takanaka, A. & Inoue, K. (1991). The Journal of Physiology 434, 647-660 | [Abstract] |
| Nakazawa, K., Ito, K., Koizumi, S., Ohno, Y. & Inoue, K. (1995). Life Sciences 57, 351-356. | |
| Searl, T. J., Redman, R. S. & Silinsky, E. M. (1998). The Journal of Physiology 510, 783-791 | [Abstract/Full Text] |
| Silinsky, E. M. & Gerzanich, V. (1993). The Journal of Physiology 464, 197-212 | [Abstract] |
| Sivilotti, L. G., McNeil, D. K., Lewis, T. M., Nassar, M. A., Schoepfer, R. & Colquhoun, D. (1997). The Journal of Physiology 500, 123-138 | [Abstract] |
| Wildman, S. S., King, B. F. & Burnstock, G. (1997). British Journal of Pharmacology 120, 221-224 | [Medline] |
| Zhou, X. &. Galligan, J. J. (1998). The Journal of Physiology 513, 685-697 | [Abstract/Full Text] |
This article has been cited by other articles:
|
|
 |
|
  B. S. Khakh, J. A. Fisher, R. Nashmi, D. N. Bowser, and H. A. Lester An Angstrom Scale Interaction between Plasma Membrane ATP-Gated P2X2 and {alpha}4{beta}2 Nicotinic Channels Measured with Fluorescence Resonance Energy Transfer and Total Internal Reflection Fluorescence Microscopy J. Neurosci., July 20, 2005; 25(29): 6911 - 6920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. North Molecular Physiology of P2X Receptors Physiol Rev, October 1, 2002; 82(4): 1013 - 1067. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
