The 5-Hydroxytryptamine(1A) Receptor Is Stably Palmitoylated, and Acylation Is Critical for Communication of Receptor with Gi Protein

In the present study, we verified that the mouse 5-hydroxytryptamine(1A) (5-HT1A) receptor is modified by palmitic acid, which is covalently attached to the protein through a thioester-type bond. Palmitoylation efficiency was not modulated by receptor stimulation with agonists. Block of protein synthesis by cycloheximide resulted in a significant reduction of receptor acylation, suggesting that palmitoylation occurs early after synthesis of the 5-HT1A receptor. Furthermore, pulse-chase experiments demonstrated that fatty acids are stably attached to the receptor. Two conserved cysteine residues 417 and 420 located in the proximal C-terminal domain were identified as acylation sites by site-directed mutagenesis. To address the functional role of 5-HT1A receptor acylation, we have analyzed the ability of acylation-deficient mutants to interact with heterotrimeric Gi protein and to modulate downstream effectors. Replacement of individual cysteine residues (417 or 420) resulted in a significantly reduced coupling of receptor with Gi protein and impaired inhibition of adenylyl cyclase activity. When both palmitoylated cysteines were replaced, the communication of receptors with Gαi subunits was completely abolished. Moreover, non-palmitoylated mutants were no longer able to inhibit forskolin-stimulated cAMP formation, indicating that palmitoylation of the 5-HT1A receptor is critical for the enabling of Gi protein coupling/effector signaling. The receptor-dependent activation of extracellular signal-regulated kinase was also affected by acylation-deficient mutants, suggesting the importance of receptor palmitoylation for the signaling through the Gβγ-mediated pathway, in addition to the Gαi-mediated signaling. In the present study, we verified that the mouse 5-hydroxytryptamine(1A) (5-HT1A) receptor is modified by palmitic acid, which is covalently attached to the protein through a thioester-type bond. Palmitoylation efficiency was not modulated by receptor stimulation with agonists. Block of protein synthesis by cycloheximide resulted in a significant reduction of receptor acylation, suggesting that palmitoylation occurs early after synthesis of the 5-HT1A receptor. Furthermore, pulse-chase experiments demonstrated that fatty acids are stably attached to the receptor. Two conserved cysteine residues 417 and 420 located in the proximal C-terminal domain were identified as acylation sites by site-directed mutagenesis. To address the functional role of 5-HT1A receptor acylation, we have analyzed the ability of acylation-deficient mutants to interact with heterotrimeric Gi protein and to modulate downstream effectors. Replacement of individual cysteine residues (417 or 420) resulted in a significantly reduced coupling of receptor with Gi protein and impaired inhibition of adenylyl cyclase activity. When both palmitoylated cysteines were replaced, the communication of receptors with Gαi subunits was completely abolished. Moreover, non-palmitoylated mutants were no longer able to inhibit forskolin-stimulated cAMP formation, indicating that palmitoylation of the 5-HT1A receptor is critical for the enabling of Gi protein coupling/effector signaling. The receptor-dependent activation of extracellular signal-regulated kinase was also affected by acylation-deficient mutants, suggesting the importance of receptor palmitoylation for the signaling through the Gβγ-mediated pathway, in addition to the Gαi-mediated signaling. Serotonin (5-hydroxytryptamine or 5-HT) 1The abbreviations used are: 5-HT5-hydroxytryptamine or serotonin5-HT1Amouse 5-hydroxytryptamine 1A receptorGPCRsG protein-coupled receptorsACadenylyl cyclaseErkextracellular signal-regulated kinase8-OH-DPAT8-hydroxy-N,N-dipropyl-2-aminotetralinPBSphosphate-buffered salineSf.9Spodoptera frugiperda insect cellsGTPγSguanosine 5′-3-O-(thio)triphosphateCHOchinese hamster ovaryWTwild typeHAhemagglutinin. is a neuromodulator involved in the regulation of many different physiological functions of the central nervous system as well as the periphery by activating a large family of receptors. With the exception of the 5-HT3 receptor, which is a transmitter-gated Na+/K+ channel, all other 5-HT receptors belong to a large family of receptors that are coupled to different intracellular effectors via heterotrimeric guanine nucleotide-binding proteins (G proteins) (1Boess F.G. Martin I.L. Neuropharmacology. 1994; 33: 275-317Google Scholar, 2Barnes N.M. Sharp T. Neuropharmacology. 1999; 38: 1083-1152Google Scholar). Structurally, G protein-coupled receptors (GPCRs) possess seven transmembrane domains linked by alternating intracellular (i1–i3) and extracellular (e1–e4) loops. The extracellular receptor surface, including the N terminus, is known to be critically involved in ligand binding. The intracellular receptor surface, including the C-terminal domain and intracellular loops (in particular i2 and i3), is known to be important for G protein recognition and activation (3Wess J. Faseb J. 1997; 11: 346-354Google Scholar). 5-hydroxytryptamine or serotonin mouse 5-hydroxytryptamine 1A receptor G protein-coupled receptors adenylyl cyclase extracellular signal-regulated kinase 8-hydroxy-N,N-dipropyl-2-aminotetralin phosphate-buffered saline Spodoptera frugiperda insect cells guanosine 5′-3-O-(thio)triphosphate chinese hamster ovary wild type hemagglutinin. The 5-HT1A receptor is the most extensively characterized 5-HT receptor. This receptor is coupled to a variety of effectors via pertussis toxin-sensitive heterotrimeric G proteins of the Gi/o families (2Barnes N.M. Sharp T. Neuropharmacology. 1999; 38: 1083-1152Google Scholar, 4Albert P.R. Vitam. Horm. 1994; 48: 59-109Google Scholar, 5Raymond J.R. Mukhin Y.V. Gettys T.W. Garnovskaya M.N. Br. J. Pharmacol. 1999; 127: 1751-1764Google Scholar). Receptor-dependent activation of Gαi subunits results in the inhibition of adenylate cyclase and subsequent decrease of cAMP levels in both hippocampal neurons (6De Vivo M. Maayani S. J. Pharmacol. Exp. Ther. 1986; 238: 248-253Google Scholar, 7Dumuis A. Sebben M. Bockaert J. Mol. Pharmacol. 1988; 33: 178-186Google Scholar) and different cell lines expressing the receptor (8Fargin A. Raymond J.R. Regan J.W. Cotecchia S. Lefkowitz R.J. Caron M.G. J. Biol. Chem. 1989; 264: 14848-14852Google Scholar, 9Liu Y.F. Albert P.R. J. Biol. Chem. 1991; 266: 23689-23697Google Scholar, 10Nebigil C.G. Garnovskaya M.N. Casanas S.J. Mulheron J.G. Parker E.M. Gettys T.W. Raymond J.R. Biochemistry. 1995; 34: 11954-11962Google Scholar). Analysis of G protein specificity for the 5-HT1A receptor revealed an unexpected complexity. Antisense depletion of different subtypes of the Gαi subunit revealed that removal of Gαi1 eliminated 5-HT1A-induced inhibition of basal cAMP levels, whereas depletion of Gαi2 and Gαi3 blocked the 5-HT1A receptor action on Gs-activated adenylyl cyclase (AC) (11Liu Y.F. Ghahremani M.H. Rasenick M.M. Jakobs K.H. Albert P.R. J. Biol. Chem. 1999; 274: 16444-16450Google Scholar). Expression studies in Sf.9 insect cells have also provided the first evidence for possible post-translational modifications of the 5-HT1A receptor (12Butkerait P. Zheng Y. Hallak H. Graham T.E. Miller H.A. Burris K.D. Molinoff P.B. Manning D.R. J. Biol. Chem. 1995; 270: 18691-18699Google Scholar). Besides effects mediated by Gαi/o subunits, activation of the 5-HT1A receptor leads to a Gβγ-mediated activation of K+ current and inhibition of Ca2+ current in hippocampal neurons (13Zgombick J.M. Beck S.G. Mahle C.D. Craddock-Royal B. Maayani S. Mol. Pharmacol. 1989; 35: 484-494Google Scholar, 14Clarke W.P. Yocca F.D. Maayani S. J. Pharmacol. Exp. Ther. 1996; 277: 1259-1266Google Scholar, 15Andrade R. Malenka R.C. Nicoll R.A. Science. 1986; 234: 1261-1265Google Scholar), dorsal raphe nucleus neurons (14Clarke W.P. Yocca F.D. Maayani S. J. Pharmacol. Exp. Ther. 1996; 277: 1259-1266Google Scholar) and atrial myocytes (16Karschin A. Ho B.Y. Labarca C. Elroy-Stein O. Moss B. Davidson N. Lester H.A. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 5694-5698Google Scholar). In CHO cells, the 5-HT1A receptor also mediates Gβγ-mediated stimulation of phospholipase C as well as activation of mitogen-activated protein kinase Erk2 (8Fargin A. Raymond J.R. Regan J.W. Cotecchia S. Lefkowitz R.J. Caron M.G. J. Biol. Chem. 1989; 264: 14848-14852Google Scholar, 17Garnovskaya M.N. van Biesen T. Hawe B. Casanas Ramos S. Lefkowitz R.J. Raymond J.R. Biochemistry. 1996; 35: 13716-13722Google Scholar). Considerable interest has been raised from pharmacological studies indicating a role for the 5-HT1A receptor in regulating anxiety states, and the production of knock-out mice lacking this receptor has confirmed these expectations (18Ramboz S. Oosting R. Amara D.A. Kung H.F. Blier P. Mendelsohn M. Mann J.J. Brunner D. Hen R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14476-14481Google Scholar, 19Heisler L.K. Chu H.M. Brennan T.J. Danao J.A. Bajwa P. Parsons L.H. Tecott L.H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15049-15054Google Scholar, 20Parks C.L. Robinson P.S. Sibille E. Shenk T. Toth M. Proc. Natl. Acad. Sci. U. S. A. 1998; Vol. 95: 10734-10739Google Scholar). The covalent attachment of fatty acids to proteins (acylation) is a widespread post-translational modification (21Resh M.D. Biochim. Biophys. Acta. 1999; 1451: 1-16Google Scholar). Two main modes of acylation have been described: N-myristoylation and palmitoylation (S-acylation). N-myristoylation is a co-translational modification catalyzed by N-myristoyltransferase, which modifies glycine residues located within a consensus sequence at the protein N terminus via an amide linkage (22Boutin J.A. Cell Signal. 1997; 9: 15-35Google Scholar). Contrary to myristoylation, the addition of long chain fatty acids (mainly palmitic acid) is a post-translational event, which occurs through covalent linkage of palmitate via a labile thioester bond to cysteine residues. In contrast to the myristoylation, the molecular machinery responsible for palmitoylation of proteins is only poorly understood. In fact, both enzymatic and nonenzymatic S-acylation have been and on protein in and provided the first of that protein palmitoylation R.J. Biochemistry. Vol. Scholar). Palmitoylation is modifications as be and the palmitoylated involved in subunits of G adenylyl and are for modification M. S. B. T. P. 1995; Scholar, Biochim. Biophys. Acta. 1998; Scholar, M. Cell Biol. Scholar). is that of palmitoylation and be critically involved in regulation of different signaling E.M. Biol. 1995; Scholar, Cell Biol. 1997; 9: Scholar, H. A. H. A. A. C. J. Scholar). In the palmitoylation has been to be responsible for a variety of functions M. S. B. T. P. 1995; Scholar, E.M. Biol. 1995; Scholar, Cell Biol. 1997; 9: Scholar, M. P. T.E. S. B. 1995; Scholar, M. T. 1995; Scholar). of palmitoylation of the receptor leads to an of basal receptor and in to stimulation S. B. H. M. J. Scholar). of palmitoylated cysteine residues in the receptor ability to to the Gi protein T. Biophys. 1997; Scholar). have that palmitoylation of the receptor is involved in the of the receptor M. Sebben M. U. A. J. Biol. Chem. 277: Scholar). palmitoylation has been revealed to be modulated by stimulation T. Biophys. 1997; Scholar, S. M. J. Biol. Chem. Scholar, M. U. J. Scholar), whereas for the receptor, the of palmitoylation was not affected by the Y. J. J. 1999; Scholar). Moreover, stimulation of modulate palmitoylation of G proteins H. M.D. E. Mol. Pharmacol. 1997; Scholar, K.H. 1995; Scholar, Manning D.R. J. Biol. Chem. Scholar, J. J.J. J. Biol. Chem. Scholar). In the present study, we that the 5-HT1A receptor is modified by covalently attached Palmitoylation efficiency was not affected by and of protein synthesis by cycloheximide resulted in a significant reduction of the receptor site-directed cysteine residues 417 and 420 located in the C terminus were identified as acylation acylation-deficient mutants, we also were able to a functional of 5-HT1A receptor palmitoylation for the coupling to the Gαi as well as with subunits and for the inhibition of forskolin-stimulated cAMP and were from Analysis and were from raised and were from used in molecular were from and were from insect cell were from The was from Cell were from were by was from were from were as by J. E. T. a Scholar). The was provided by R. Albert The was with C and to acids at the N terminus of the receptor. The was to the of the sites of or of the 5-HT1A receptor with the of for cysteine at 417 420 was by an the to the E. C. 1998; Scholar). The for mutants were and as M. B. C. E. 1994; Scholar). mutants were verified by of the and frugiperda cells were in with and Sf.9 cells in were with for 5-HT1A receptor at a of of Sf.9 cells were with or for the in In 5-HT or were to the as in To protein cycloheximide was to with or the pulse-chase experiments cells were with with palmitate and cells were with and in of was and were to the at a of at of protein was and were for the was with and the were from the by for at in and were analyzed by on and by of was by and the 5-HT1A receptor with were acid, and with or were in and for in to fatty acids were for the fatty the 5-HT1A receptor was by and The to the receptor protein was and fatty acids were by of the with for at acids were with and individual fatty by as fatty was by after with 5-HT1A or with Sf.9 cells on were with in for The cells were with and was with glycine for were with and for with the in The from in was for and were at with were in were a of the receptors in CHO cells was analyzed as by M. Sebben M. U. A. J. Biol. Chem. 277: Scholar). for of to different G proteins by stimulation of 5-HT1A receptors was to the E. C. 1998; Scholar). from Sf.9 cells expressing the 5-HT1A receptor or acylation-deficient mutants and G protein subunits with subunits were in of and to a of were for at in the or of The was by of and for on were for at after addition of of of protein and of and were from the of subunits, E. C. 1998; Scholar) was were in of and was by for from Sf.9 cells expressing or 5-HT1A receptors were in and The with was as (12Butkerait P. Zheng Y. Hallak H. Graham T.E. Miller H.A. Burris K.D. Molinoff P.B. Manning D.R. J. Biol. Chem. 1995; 270: 18691-18699Google Scholar, M.D. S. M. H. J. Scholar). of acid, and of was to of the was by addition of a at the was on in The were with and was by were with the by the of Scholar). Cell and cAMP 5-HT1A receptor and acylation-deficient mutants were in and in cells by were in and after cells were in to the were and in of the in the for at The was by the with of The cAMP was as A. Sebben M. Bockaert J. Mol. Pharmacol. 1988; 33: 178-186Google Scholar). The of the 5-HT1A receptor was as in A. Y. Bockaert J. Mol. Pharmacol. Scholar). Erk2 cells were in with and CHO cells in were with 5-HT1A receptor to the after cells were in with and for were for with at with and in the of proteins in were by and to The were with raised or To the receptor were with raised the To the of of was in of the and the were by The of the and receptors was to of as by binding. was in the of of 5-HT1A receptor Expression and Palmitoylation of the 5-HT1A the of the 5-HT1A receptor with an at the N terminus was as and used for of Sf.9 insect In to the and of the receptor, Sf.9 cells were to The 5-HT1A receptors were by and at the cell with by and revealed a protein with a molecular of This to the molecular of the 5-HT1A receptor. The of in the from or Sf.9 cells confirmed that the the 5-HT1A receptor. To the 5-HT1A receptor is Sf.9 cells with were with revealed a of only in cells with the This that the 5-HT1A receptor that the 5-HT1A receptor is we on to the of the fatty bond in to and fatty in the was to with of Moreover, of 5-HT1A receptors with resulted in a of the from the receptor results that the 5-HT1A receptor and no fatty acids linked through amide or To the of fatty the receptor was to the fatty fatty acids were from the protein and by Analysis of the revealed that the 5-HT1A receptor only palmitate with no of or of the 5-HT1A have demonstrated that palmitoylation of the other of the serotonin receptor the receptor, is a and that receptor stimulation by the of palmitate M. U. J. Scholar). To palmitoylation of the 5-HT1A receptor also be by the Sf.9 cells expressing the receptor were with of 5-HT the cells with The results in that stimulation with the not in of receptor with in demonstrated that the of the receptor was not affected to the In to the of we the of of 5-HT1A receptors. in the of the receptor the a basal of The of was in the of The results in that to the not the efficiency of the The of the on receptor palmitoylation was analyzed after of the 5-HT1A receptor with Gi protein and In coupled stimulation has no on the efficiency receptor palmitoylation To the role of protein synthesis in receptor Sf.9 cells expressing 5-HT1A receptors were with or in the or of this revealed that of protein synthesis results in inhibition of the receptor The of cycloheximide was not in the of the To fatty acids a long pulse-chase experiments were in the of to the of the receptor that no of fatty from the receptor occurs the these that palmitoylation of the 5-HT1A receptor is not to the stimulation and that acylation is a modification to a of the receptors. of Palmitoylation to the palmitoylation within the 5-HT1A receptor, we a of receptors in which C-terminal cysteine residues 417 420 were by mutants were in Sf.9 insect cells by the system and with or by and with revealed that the receptors were with the receptor also the of palmitate for individual mutants by of after in to the by of or resulted in a significantly not completely blocked The of palmitoylation that of the and mutants was and in which both cysteine residues were by not of after of the we that both cysteine residues and palmitoylation sites on the 5-HT1A receptor. of Palmitoylation in of the with G for the functional of receptor we analyzed of the 5-HT1A receptor with different subunits of heterotrimeric G protein by the coupling E. C. 1998; Scholar). subunits were with the receptor in Sf.9 cells (in all the subunit was with and and of to the subunit was by after with When the 5-HT1A receptor was with or we an to in stimulation with The confirmed that the 5-HT1A receptor with G proteins of the Gi In was no coupling after of the receptor with or the ability of receptor mutants to to Gαi In the of mutants and was significantly with the receptor. activation of Gαi the basal was In the non-palmitoylated receptor was the activation of Gαi3 subunit after stimulation was completely is that the 5-HT1A receptor, all mutants and Gαi3 subunits were in a as by experiments also analyzed the pharmacological for the receptor and that was to that for this receptor in insect cells H.M. Parker E.M. S.G. Biochemistry. 1997; Scholar). of the mutants revealed that of palmitoylated cysteines not pharmacological The of for 5-HT1A receptors was to that for the and these a functional importance of 5-HT1A receptor palmitoylation for the coupling to Gi of the of the 5-HT1A to the in experiments with Sf.9 insect cells the importance of acylation for of the receptor with Gi protein we the functional role of 5-HT1A receptor palmitoylation in a cell analyzed the ability of and receptors to inhibit the forskolin-stimulated cAMP of the 5-HT1A receptor M. S. H. M.D. C. J. Pharmacol. Scholar). a system we used cells that not sites A. Y. Bockaert J. Mol. Pharmacol. Scholar). cells were with the for and the acylation-deficient mutants of the 5-HT1A receptor. The for the and all mutants was to which for a of Expression of the 5-HT1A receptor resulted in significant inhibition of cAMP receptor stimulation with in a Replacement of of the palmitoylation sites was by a significant decrease in the of receptors to inhibit forskolin-stimulated cAMP the inhibition of cAMP for the 5-HT1A receptor was for the mutants and this was reduced to and In the of the 5-HT1A receptor the of the receptor was completely and to no on the intracellular cAMP Analysis of the inhibition of cAMP of revealed that the for the mutants was that for the 5-HT1A receptor. an of for the for the mutants and for the confirmed the results for Gαi3 coupling in Sf.9 insect cells and to a functional of 5-HT1A receptor palmitoylation in the Gαi-mediated signaling. of and in CHO the intracellular of the and 5-HT1A the for the proteins were in a and in CHO To and intracellular of cells were to with in were no in the and receptors. This that palmitoylation not critically to the intracellular of the 5-HT1A receptors. by 5-HT1A and addition to Gαi-mediated inhibition of the the 5-HT1A receptor modulate the of via M.N. van Biesen T. Hawe B. Casanas Ramos S. Lefkowitz R.J. Raymond J.R. Biochemistry. 1996; 35: 13716-13722Google Scholar). we analyzed the ability of 5-HT1A receptor and acylation-deficient mutants to by with of In the of and 5-HT1A receptor was verified by a with or The for the and all receptors was to which for a of that of CHO cells with 5-HT1A receptor resulted in an and activation of the acylation mutants and we decrease of activation of in with the receptor. In the of with only a in of the importance of receptor palmitoylation for signaling through the Gβγ-mediated pathway, in addition to the Gαi-mediated signaling. attachment of palmitic to proteins is a and acylation has been demonstrated for a of signaling Moreover, palmitoylation of including and and have been to be by the M. S. B. T. P. 1995; Scholar, T. Biophys. 1997; Scholar, T.E. M. Biochemistry. 1996; 35: Scholar, J. Biol. Chem. 1994; Scholar, B. Caron M. M. M. J. Pharmacol. 1994; Scholar). the receptor, we have also demonstrated that stimulation the of the palmitate M. U. J. Scholar). In the present we palmitoylation of other of the 5-HT receptor the 5-HT1A receptor and the to the for the receptor, stimulation of the 5-HT1A receptor not in palmitoylation efficiency has been that the 5-HT1A receptor to proteins in insect cells J.G. Casanas S.J. J.M. Garnovskaya M.N. Gettys T.W. Raymond J.R. J. Biol. Chem. 1994; Scholar), we that palmitoylation physiological Moreover, results after of Sf.9 cells with Gi of 5-HT1A palmitoylation also in a coupled of cells with an of protein to of the receptor, indicating no significant of palmitate Furthermore, results of long pulse-chase experiments that the of fatty acids were stably attached to the receptor suggesting that palmitoylation of the 5-HT1A receptor is a a and palmitoylation is for which of the 5-HT1A receptor a C terminus of only and this be a possible for the of a for the recognition by the the of the palmitate within the with the of a acids to the the of palmitoylated is known that acylation occurs on cysteine residues located in the C-terminal domain of the receptors R. M. Pharmacol. Ther. Scholar). the 5-HT1A receptor we also identified C-terminal cysteine residues and as palmitoylation sites of acylation-deficient 5-HT1A mutants revealed that palmitoylation at or was to of receptor with the Gi to a significantly the receptor and of both palmitoylation sites completely indicating that palmitoylation of the 5-HT1A receptor is critically involved in activation of the Gαi This is with the importance of palmitoylation of and receptors for an coupling to and to both and Gαi S. B. H. M. J. Scholar, M. Caron M.G. Lefkowitz R.J. M. J. Biol. Chem. 1989; 264: Scholar, Y. H. M. A. S. T. J. Pharmacol. 1998; Scholar). on and receptors also demonstrated that receptor palmitoylation is significantly involved in activation of intracellular signaling C. J.M. A. B. B. E. C. M. J. Biol. Chem. Scholar, J. Biol. Chem. Scholar). the other this is in contrast with the results we for the receptor. we that palmitoylation was not critically involved in the coupling receptor and protein after results have been also for the receptor, which to both as well as Gi J. Biol. Chem. Scholar). In the of the receptor, has also been that C-terminal is not for inhibition of N.M. J. 1991; Scholar) ability of the receptor to Gi T. Biophys. 1997; Scholar). that is no acylation to all and of individual receptor is palmitoylation of the 5-HT1A receptor communication receptor and Gi the intracellular as well as pharmacological of mutants were to for the receptor we the in intracellular receptor and as possible for impaired Gi protein are in which palmitoylation the receptor palmitoylation be for the receptor to the for the protein recognition or for G protein activation or the palmitoylation be for receptor to the has been that palmitoylation of a to an intracellular in the C-terminal of the receptor E.M. Biol. 1995; Scholar, M. P. T.E. S. B. 1995; Scholar). evidence for this has been for S.J. J. Biochemistry. 1994; 33: Scholar, T. T. H. T. M. M. Science. Scholar). the 5-HT1A receptor acylation within the C-terminal domain receptor palmitoylation in the of an intracellular as in The that the 5-HT1A receptor in a palmitoylation a and with the be by acids palmitoylated cysteine residues to the for (21Resh M.D. Biochim. Biophys. Acta. 1999; 1451: 1-16Google Scholar, P.B. Biol. Signal. 1998; Scholar), of the palmitate and of the intracellular C-terminal domain with the the of the C-terminal domain a important for the communication with Gi of acylation in of the receptor C terminus with the be for with Gi protein in the coupling efficiency be Replacement of both palmitoylated cysteines the and the receptor activity. be the of 5-HT1A receptor palmitoylation in to the palmitoylation has been to be important for the of proteins in and M.G. D.A. J. Biol. Chem. 1999; 274: Scholar, S. D.A. J. Biol. Chem. Scholar, R. D. S.J. J. Scholar, J. Biol. Chem. Scholar, P. M. A. M. J. Cell Biol. Scholar, Biol. 35: Scholar, M. C. S. A. J. Scholar, A. J. Biol. Chem. Scholar). that palmitoylation of the 5-HT1A receptor a for be that the removal of or both palmitate from the 5-HT1A receptor with have been to different of a particular signaling system for signaling C. J.R. Mol. Biol. 1997; Scholar), of the 5-HT1A receptor in from cyclase signaling studies be to palmitoylation of the 5-HT1A receptor a role in the receptor or is involved in Albert from the of at the of for the receptor

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