Effect of Membrane Lipid Composition on the Conformational Equilibria of the Nicotinic Acetylcholine Receptor

The effects of cholesterol (Chol) and an anionic lipid, dioleoylphosphatidic acid (DOPA) on the conformational equilibria of the nicotinic acetylcholine receptor (nAChR) have been investigated using Fourier transform infrared difference spectroscopy. The difference between spectra recorded in the presence and absence of agonist from the nAChR reconstituted into 3:1:1 egg phosphatidylcholine (EPC)/DOPA/Chol membranes exhibits positive and negative bands that serve as markers of the structural changes associated with the resting to desensitized conformational change. These markers are absent in similar difference spectra recorded from the nAChR reconstituted into EPC membranes lacking both Chol and DOPA, indicating that the nAChR cannot undergo conformational change in response to agonist binding. When low levels of either Chol or DOPA up to 25 mol % of the total lipid are included in the EPC membranes, the markers suggest the predominant stabilization of a conformation that is a structural intermediate between the resting and desensitized states. At higher levels of either Chol or DOPA, the nAChR is stabilized in a conformation that is capable of undergoing agonist-induced desensitization, although DOPA appears to be required for the nAChR to adopt a conformation fully equivalent to that found in native and 3:1:1 EPC/DOPA/Chol membranes. The ability of these two structurally diverse lipids, as well as others (Ryan, S. E., Demers, C. N., Chew, J. P., Baenziger, J. E. (1996) J. Biol. Chem. 271, 24590–24597), to modulate the functional state of the nAChR suggests that lipids act on the nAChR via an indirect effect on some physical property of the lipid bilayer. The data also suggest that anionic lipids are essential to stabilize a fully functional nAChR. We propose that membrane fluidity modulates the relative populations of nAChRs in the resting and desensitized states but that subtle structural changes in the presence of anionic lipids are essential for full activity. The effects of cholesterol (Chol) and an anionic lipid, dioleoylphosphatidic acid (DOPA) on the conformational equilibria of the nicotinic acetylcholine receptor (nAChR) have been investigated using Fourier transform infrared difference spectroscopy. The difference between spectra recorded in the presence and absence of agonist from the nAChR reconstituted into 3:1:1 egg phosphatidylcholine (EPC)/DOPA/Chol membranes exhibits positive and negative bands that serve as markers of the structural changes associated with the resting to desensitized conformational change. These markers are absent in similar difference spectra recorded from the nAChR reconstituted into EPC membranes lacking both Chol and DOPA, indicating that the nAChR cannot undergo conformational change in response to agonist binding. When low levels of either Chol or DOPA up to 25 mol % of the total lipid are included in the EPC membranes, the markers suggest the predominant stabilization of a conformation that is a structural intermediate between the resting and desensitized states. At higher levels of either Chol or DOPA, the nAChR is stabilized in a conformation that is capable of undergoing agonist-induced desensitization, although DOPA appears to be required for the nAChR to adopt a conformation fully equivalent to that found in native and 3:1:1 EPC/DOPA/Chol membranes. The ability of these two structurally diverse lipids, as well as others (Ryan, S. E., Demers, C. N., Chew, J. P., Baenziger, J. E. (1996) J. Biol. Chem. 271, 24590–24597), to modulate the functional state of the nAChR suggests that lipids act on the nAChR via an indirect effect on some physical property of the lipid bilayer. The data also suggest that anionic lipids are essential to stabilize a fully functional nAChR. We propose that membrane fluidity modulates the relative populations of nAChRs in the resting and desensitized states but that subtle structural changes in the presence of anionic lipids are essential for full activity. nicotinic acetylcholine receptor carbamylcholine desensitized resting dioleoylphosphatidylcholine cholesterol dioleoylphosphatidic acid egg phosphatidylcholine Fourier transform infrared attenuated total reflectance The nicotinic acetylcholine receptor (nAChR)1 fromTorpedo is a large multisubunit integral membrane protein that has been used extensively as a model for studying the mechanisms of lipid-protein interactions (1.Miyazawa A. Fujiyoshi Y. Stowell M. Unwin N. J. Mol. Biol. 1999; 288: 765-786Crossref PubMed Scopus (430) Google Scholar, 2.McNamee M.G. Fong T.M. Aloia R.C. Curtain C.C. Gordon L.M. Lipid Domains and the Relationship to Membrane Function. Alan R. Liss, Inc., New York1988: 43-62Google Scholar). In native membranes, the nAChR transiently gates open a cation-selective ion channel across the postsynaptic membrane in response to the binding of agonists such as acetylcholine and carbamylcholine (Carb). Prolonged exposure to either agonist or a variety of noncompetitive antagonists leads to the stabilization of a channel inactive/desensitized (D) state. In reconstituted membranes, the ability of the nAChR both to conduct cations across the membrane and to undergo the resting to desensitized (R→D) conformational transition is highly sensitive to the composition of the surrounding lipid membrane. The molecular details of how lipids modulate the ability of the nAChR to undergo agonist-induced conformational change, however, remain unclear. The original studies of Fong and McNamee (3.Fong T.M. McNamee M.G. Biochemistry. 1986; 26: 3871-3880Crossref Scopus (111) Google Scholar) suggested that although the nAChR reconstituted into a dioleoylphosphatidylcholine (DOPC) membrane is not functional, the addition of both cholesterol (Chol) and an anionic lipid, such as dioleoylphosphatidic acid (DOPA), to the reconstituted DOPC membrane restores the ability of the nAChR both to conduct cations and undergo agonist-induced desensitization. The recovery of function in the presence of Chol and DOPA was attributed to both the formation of a lipid bilayer with an optimal membrane fluidity and a specific structural requirement of the nAChR for each lipid. The latter was proposed to result from the binding of each to distinct sites on the nAChR with the consequent formation of specific secondary structural features (3.Fong T.M. McNamee M.G. Biochemistry. 1986; 26: 3871-3880Crossref Scopus (111) Google Scholar, 5.Butler D.H. McNamee M.G. Biochim. Biophys. Acta. 1993; 1150: 17-24Crossref PubMed Scopus (40) Google Scholar, 6.Bhushan A. McNamee M.G. Biophys. J. 1993; 64: 716-723Abstract Full Text PDF PubMed Scopus (48) Google Scholar, 7.Fernandez-Ballester G. Castresana J. Fernandez A.M. Arrondo J.L.R. Ferragut J.A. Gonzalez-Ros J.M. Biochemistry. 1994; 33: 4065-4071Crossref PubMed Scopus (69) Google Scholar). Subsequent work has led to contradictory conclusions regarding the additional lipids that are required in a reconstituted DOPC membrane for the nAChR to adopt a functional conformation. McCarthy and Moore (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar) proposed that anionic lipids are sufficient to stabilize a functional nAChR on and binding studies of the nAChR in membranes of egg phosphatidylcholine and work also found that reconstituted into membranes of either or EPC the nAChR a conformation (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). In the binding of suggest that of a functional nAChR in either or DOPC the nAChR is in an conformation also Biochim. Biophys. Acta. PubMed Scopus Google Scholar). Fourier transform infrared difference spectra are with the data of McCarthy and Moore (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar) in that suggest that the nAChR in EPC is desensitized J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In to both the data that the presence of of either or anionic lipids in an EPC membrane is sufficient to stabilize a of the nAChRs in a functional conformation that is capable of undergoing agonist-induced conformational change. The data led to the that lipids modulate the relative of nAChRs in the and states in the absence of The ability of a variety of structurally diverse and anionic lipids to modulate the between the and suggests that lipids nAChR conformational equilibria via an indirect effect on some physical property of the membrane. of a variety of structurally diverse and anionic lipids in DOPC membranes nAChR C. McNamee M.G. Biochim. Biophys. Acta. 1994; PubMed Scopus Google Scholar). studies have also been to of the changes in nAChR secondary in the presence of anionic lipids N. Biochemistry. PubMed Scopus Google Scholar). The contradictory conclusions in the regarding the specific lipid of the nAChR a variety of the that the functional of the nAChR in studies has been in reconstituted DOPC or EPC membranes with the additional lipid of found a of the total membrane lipids or In functional data have also been in of the stabilization of either a fully functional or a conformation. the that lipids modulate the equilibria between conformational states. The relative of a lipid in a reconstituted phosphatidylcholine membrane be an in the relative of nAChRs stabilized in a functional conformation the of nAChR conformational change. a of the specific lipid of the nAChR and to the regarding a of nAChR conformational have the ability of the nAChR to undergo the conformational change in EPC membranes with levels of either DOPA or We that levels of either lipid in an EPC membrane a of nAChRs in a that capable of undergoing desensitization. levels of DOPA found to stabilize a of the nAChR is fully equivalent to that found in native and 3:1:1 EPC/DOPA/Chol membranes. These suggest that the presence of either DOPA or Chol in a reconstituted EPC membrane the between the and conformational states but that anionic lipids are required for the nAChR to adopt a fully functional conformation. EPC and DOPA from lipids, and the Chol was from was from The was from and from and to M. A. Biophys. PubMed Scopus Google Scholar). The infrared of the was on a similar of G. A. Biochemistry. PubMed Scopus Google Scholar). E. Baenziger, and J. The nAChR was on a and reconstituted into membranes of EPC with levels of either DOPA or as McCarthy and Moore (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). In for the of and each was between two and of the nAChR protein in on the of a attenuated total reflectance the with a of the was in an from and the nAChR with and spectra using the on an with a recorded using the difference two state spectra of the nAChR in the absence of recorded with the of the a of The was to an a of the state was The difference between both the two state spectra of and the and of state spectra and the to a to from the and the nAChR into the the was was on from each difference spectra between and and to an of details and Mol. 1999; PubMed Scopus Google Scholar). The difference between infrared spectra of the nAChR recorded in the presence and absence of to as a difference exhibits a of positive and negative These difference bands changes in the of acid in the nAChR surrounding change binding. The of difference bands a of the structural changes that in the nAChR. features the of to the nAChR in the of changes associated with the formation of physical interactions between and binding and changes associated with the conformational change. The conformational change in a difference is in difference spectra recorded from nAChR reconstituted into membranes of 3:1:1 a membrane that to a (3.Fong T.M. McNamee M.G. Biochemistry. 1986; 26: 3871-3880Crossref Scopus (111) Google are similar to recorded from the nAChR in native membranes and the of difference bands for a functional nAChR in difference spectra recorded from the nAChR reconstituted into EPC membranes lacking and anionic lipids are similar but a of in These subtle changes in the of the nAChR and a in the of positive bands and The in of a positive to the in of the negative and in Mol. 1999; PubMed Scopus Google Scholar). the bands in the difference spectra remain to be to specific is that the changes in are in difference spectra recorded from the nAChR in 3:1:1 EPC/DOPA/Chol membranes in with such as In low of the stabilize the nAChR in an as to a to an as to a in the of the difference suggest that the positive difference bands changes in as a of the conformational transition a Mol. 1999; PubMed Scopus Google Scholar). The absence of these bands in difference spectra recorded from the nAChR reconstituted into EPC membranes that the nAChR in membrane not undergo the conformational transition the binding of result is with that the nAChR in EPC is stabilized in the state (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). In addition to the changes subtle changes between and and and and in in the are to of the difference spectra recorded using acetylcholine on the of to the conformational transition The difference spectra a in the for protein difference spectra recorded from the nAChR in EPC/DOPA/Chol both a negative and positive difference and changes in the of either a or a lipid The is absent in difference spectra recorded from the nAChR reconstituted into EPC membranes in between and and between and are to of the of that in these the of the difference of changes in these with in spectra recorded in the presence of are also negative bands to of from the binding in the latter spectra is to both or not these changes are the changes are associated with the conformational change. on the bands that are and difference spectra recorded from the nAChR reconstituted into membranes of EPC with of the anionic lipid DOPA a in positive the sensitive and In the in these are low levels of DOPA up to the of higher levels of DOPA are The of sensitive bands in the difference spectra recorded from the nAChR in both the and in difference spectra recorded from the nAChR in 3:1:1 EPC/DOPA/Chol membranes. In the difference spectra recorded from the nAChR in membranes a negative and positive and The difference spectra that the nAChR in both the and ability to undergo the conformational transition and be stabilized in a functional conformation. In of levels of DOPA in an EPC membrane to be sufficient to stabilize the nAChR in a functional conformation that is equivalent to that found in 3:1:1 EPC/DOPA/Chol membranes, in the absence of that the nAChR in EPC membranes is stabilized in a state data are with a in the the state with levels of of the data that the effects of DOPA be the of a conformational The difference spectra recorded from the nAChR in both the and membranes large positive and relative to the of the bands in spectra recorded from the nAChR in EPC and In the of the two and and are similar to the of the two bands in the difference spectra recorded from the nAChR in EPC membranes lacking of suggests that a large of the sensitive in the nAChR to the difference and adopt an conformation in membranes, the of the that to the difference bands and adopt a conformation. The and membranes to stabilize a conformation that is a structural intermediate between the and states. that intermediate of has been in difference spectra recorded from the nAChR in EPC/DOPA/Chol membranes, but the nAChR is in the presence of of binding to the noncompetitive the ion channel Mol. 1999; PubMed Scopus Google Scholar). similar of is also in difference spectra recorded from the nAChR in both and membranes J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google of the changes in and in difference spectra recorded from the nAChR reconstituted into EPC membranes with levels of either DOPA or Chol In both the and to the of these two bands in difference spectra recorded from the nAChR reconstituted into EPC and 3:1:1 EPC/DOPA/Chol membranes, The are sensitive to both and are to be a of either DOPA or the relative changes in the two have a higher difference spectra recorded from the nAChR reconstituted into EPC membranes with of the lipid Chol are similar to recorded from the nAChR in EPC membranes with levels of is a in the of of the sensitive bands and The of these bands in the difference spectra recorded from the nAChR in the of recorded from the nAChR in 3:1:1 that the nAChR for the an conformation. The membranes also to stabilize a conformational intermediate between the and states as the large positive the and however, subtle between the difference spectra recorded in the presence of of DOPA and Chol suggest in the of these two lipids to modulate conformational equilibria of the nAChR. equivalent levels of either DOPA or Chol in the EPC membranes, the presence of DOPA leads to a of the sensitive bands and that DOPA is the the conformation result is in with the studies of McCarthy and suggest that the nAChR in is in the in is in the conformation (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). of Chol have effect on the of the difference At levels of the the as the of the in difference spectra recorded from the nAChR in EPC In the of in difference spectra recorded from the nAChR in either 3:1:1 or of The presence of Chol also not to difference spectra with negative to that in spectra recorded from the nAChR in both 3:1:1 EPC/DOPA/Chol and membranes The of an effect of Chol on the of these two that are subtle structural between the nAChR in EPC membranes either with or anionic lipids the difference spectra recorded from the nAChR reconstituted into are similar to recorded from the nAChR in In the of each of the sensitive difference bands and with Chol is levels of in the of difference changes suggests that the ability of Chol to stabilize the nAChR in an conformation is levels of similar in is with the of the nAChR into EPC membranes with levels of Chol Biochemistry. 1999; PubMed Scopus Google Scholar). The of work was to the that the nAChR and anionic lipids in surrounding membrane in to adopt a functional conformation that undergo agonist-induced conformational change. We have that the difference between spectra of the nAChR recorded in the presence and absence of exhibits positive and negative bands that serve as markers of the ability of the nAChR to undergo the conformational transition J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. 1999; PubMed Scopus Google Scholar). These markers are absent in difference spectra recorded from the nAChR reconstituted into EPC membranes. The absence of both and anionic lipids from a reconstituted EPC membrane leads to a receptor that cannot undergo conformational change. In these markers are with in difference spectra recorded from the nAChR reconstituted into EPC membranes with levels of either DOPA or DOPA and Chol the ability of the nAChR to undergo conformation change in response to the binding of The of either Chol or DOPA in the reconstituted however, is a in the of that lipid in a The changes in the of bands in difference spectra recorded from the nAChR reconstituted into EPC membranes with levels of either DOPA or Chol suggest features regarding the mechanisms of lipid the nAChR. These features have been into the model in The of model is that lipid composition the between the and states in the absence of agonist via an indirect effect on some physical property of the lipid membrane We also suggest that anionic lipids, in addition to a membrane are required to stabilize a fully functional nAChR. The model is on the and The that lipid composition nAChR conformational equilibria is on the that the nAChR in EPC not undergo conformational change, in the presence of levels of either DOPA or an of the ability to undergo desensitization. The stabilization of a state in as suggested the for the that the nAChR cannot undergo conformational change. in the conformational the state with levels of either DOPA or Chol for the of that undergo conformational change in response to the binding of however, that data are also with a conformation in EPC is not to as was suggested M.A. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). We not the latter for two the of the nAChR in EPC membranes the sensitive is similar to that for the nAChR in both native and 3:1:1 EPC/DOPA/Chol membranes to and (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). These that the nAChR in EPC is not in an state as proposed M.A. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). suggest that lipid composition has effect on nAChR conformational equilibria M.A. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). In the absence of a change in the relative populations found in the and the nAChR be in the conformation in EPC the between the and conformational states are that the of and In such a conformational on a in the presence of Chol and DOPA each lipid the between conformational states. of from either the formation of specific physical interactions between each lipid and the in a similar to that with to and or a effect on some property of the membrane. the formation of specific interactions between either Chol or DOPA and the nAChR to however, is the diverse of these two lipids as well as the structural of the nAChR for and anionic lipids change in some property of the lipid membrane to is also a change in property with levels of either DOPA or Chol to a change in and a change in the of between the and conformational states. The data suggest that the of nAChRs capable of undergoing conformational change, not the of the conformational changes is lipid effect of DOPA and Chol on the between the nAChR conformational states the nAChR cannot be in an state in EPC membranes. The of data is in of a lipid of the of in the and states in the absence of of model is that lipids the equilibria between conformational states of the nAChR a effect on some property of the membrane. is on the that the addition of either DOPA, or to reconstituted EPC membrane nAChR conformational equilibria J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of a variety of diverse and anionic lipids are capable of DOPA and Chol in a functional nAChR C. McNamee M.G. Biochim. Biophys. Acta. 1994; PubMed Scopus Google Scholar). Chol to a in the lipid is as as Chol in a that the sites proposed and McNamee McNamee M.G. Biochemistry. PubMed Scopus Google Scholar) are not M.A. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). Chol sites on the of the nAChR in a J. M.P. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). specific Chol binding sites on the nAChR are to the ability of Chol to nAChR both the structural of the nAChR for and anionic lipids and the of specific Chol binding sites are of an indirect effect of lipids on of the lipid membrane. We propose that both Chol and DOPA modulate nAChR conformational equilibria the membrane fluidity as in is well that the presence of Chol in a reconstituted membranes the nAChR G. Castresana J. Fernandez A.M. Arrondo J.L.R. Ferragut J.A. Gonzalez-Ros J.M. Biochemistry. 1994; 33: 4065-4071Crossref PubMed Scopus (69) Google leads to an of the and a in fluidity of Inc., Scholar). the effects of DOPA on the physical of EPC membranes are not well is that the leads to a of the lipid and an of the lipid bilayer A. J.M. J. Chem. Scopus Google Scholar, S. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). In of the has been that levels of DOPA in reconstituted EPC membranes to a in the of lipid that are to to a of into the lipid of the bilayer as a result of a of the Biochemistry. 1999; PubMed Scopus Google Scholar). a for membrane fluidity in nAChR function has been molecular from studies of the nAChR in reconstituted membranes are not with a between fluidity and function C. McNamee M.G. Biochim. Biophys. Acta. 1994; PubMed Scopus Google Scholar). a the of of a in a lipid bilayer not be sufficient to the and of the lipids and the membrane be to the and for each of lipid as well as such as lipid studies using state are in to the of membrane fluidity in the conformational equilibria of the nAChR. of model is that the nAChR the specific presence of anionic lipids, in addition to the membrane fluidity in to adopt a fully functional conformation. is on the that difference spectra recorded from the nAChR in membranes levels of DOPA are equivalent to recorded from the nAChR in functional 3:1:1 EPC/DOPA/Chol and native membranes, the difference spectra recorded from the nAChR in EPC membranes with levels of Chol are the difference spectra recorded from the nAChR in not the and are in difference spectra recorded from the nAChR in either 3:1:1 or membranes. The of these subtle to be but that in the nAChR are not found in a fully functional conformation in the absence of anionic data from also suggest that the nAChR in with in a equivalent to that with the nAChR in 3:1:1 in membranes in the interactions are E. and J. E. Baenziger, suggests that subtle in the difference spectra recorded from the nAChR in EPC membranes either with or DOPA with functional for the nAChR. We to the and of the nAChR stabilized in the absence of anionic lipids as and The ability of membranes to a functional nAChR is with the work of McCarthy and that the nAChR in membranes is capable of undergoing agonist-induced conformational change (8.McCarthy M.P. Moore M.A. J. Biol. Chem. 1992; 267: 7655-7663Abstract Full Text PDF PubMed Google Scholar). as the nAChR in a in response to the binding of C. McNamee M.G. Biochim. Biophys. Acta. 1994; PubMed Scopus Google Scholar, McNamee M.G. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). In to studies have that the nAChR has an structural requirement for studies to the functional state of the nAChR in the presence of anionic lipids have nAChR function in DOPC membranes with the anionic lipid of a of or of the total a of the nAChR in EPC membranes or DOPA is stabilized in a functional state with the low in similar membranes. also be that the used others are the used has two EPC has to a of the nAChRs in a state. is to that the nAChR in not in with the nAChR cations G. Castresana J. Fernandez A.M. Arrondo J.L.R. Ferragut J.A. Gonzalez-Ros J.M. Biochemistry. 1994; 33: 4065-4071Crossref PubMed Scopus (69) Google Scholar). The latter that a Chol is for the nAChR to adopt a functional state. data suggest that the levels of Chol in both of these membranes a The in the be an anionic lipid, such as The specific anionic lipids nAChR conformation to be The of model is that lipids the conformational equilibria between a and a state. is on the that the difference spectra recorded from the nAChR in and membranes a of bands is of the stabilization of the nAChR in a conformation that is a structural intermediate between the and states. the spectra recorded from the nAChR in both membranes of the sensitive and are similar to in difference spectra recorded from the nAChR in EPC membranes the and are to that found in difference spectra recorded from the nAChR in 3:1:1 At these low levels of either anionic or lipids, some of the nAChR adopt a others adopt an conformation. that the of is in difference spectra recorded from the nAChR in EPC/DOPA/Chol membranes the nAChR is to of to binding to the noncompetitive in the ion channel Mol. 1999; PubMed Scopus Google Scholar). the equilibria conformational states of the nAChR. The data the of the mechanisms lipids nAChR These have been into the model in for in the regarding the effects of lipids on nAChR such as the surrounding the nAChR also an M. M. A. Biochemistry. PubMed Scopus (40) Google Scholar). model that be with fully the mechanisms of lipid-protein interactions the however, studies of the effects of lipids on nAChR and function in with of the physical of reconstituted nAChR membranes be We have reconstituted the nAChR into EPC membranes with levels of either DOPA or The levels of either lipid stabilize the nAChR in a conformation that is capable of undergoing conformational change, although DOPA the nAChR in appears to be a fully functional state. We in of a model that the mechanisms lipids nAChR We suggest that membrane fluidity or some property of the membrane modulates the between the and states. membrane with a low fluidity be required to stabilize the nAChR in the functional a membrane to the stabilization of the state. At conformational intermediate between the and states the model suggests that in addition to an indirect effect of lipids via the the nAChR anionic lipids such as DOPA, but not to adopt a fully functional conformation. specific lipid requirement for anionic lipids result from either the binding to a specific on the nAChR or a specific effect of on nAChR conformation.

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