Molecular Endocrinology, doi:10.1210/me.2006-0066
Molecular Endocrinology 20 (12): 3035-3041
Copyright © 2006 by The Endocrine Society
Protein Folding as Posttranslational Regulation: Evolution of a Mechanism for Controlled Plasma Membrane Expression of a G Protein-Coupled Receptor
P. Michael Conn,
Paul E. Knollman,
Shaun P. Brothers and
Jo Ann Janovick
Divisions of Neuroscience and Reproductive Biology (P.M.C., P.E.K., S.P.B., J.A.J.), Oregon National Primate Research Center and Departments of Physiology and Pharmacology (P.M.C., S.P.B.) and Cell and Developmental Biology (P.M.C.), Oregon Health and Science University, Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: P. Michael Conn, Oregon National Primate Research Center/Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon, 97006. E-mail: connm{at}ohsu.edu.
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ABSTRACT
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Recent studies reveal that a number of G protein-coupled receptors (GPCRs) and other proteins are expressed inefficiently at the site normally associated with their biological action. In the case of some GPCRs, large amounts of receptor (perhaps more than half) may be destroyed without ever binding ligand or even arriving at the plasma membrane. For the human GnRH receptor (GnRHR), this apparent inefficiency has evolved under strong and convergent evolutionary pressure. The result is a human GnRHR molecule that is delicately balanced between either expression at the plasma membrane (PM) or retention/degradation in the endoplasmic reticulum, an effect mediated by engagement with the cellular quality control system. This balance appears to be the reason that the human receptor, but not the rat or mouse counterpart (which are more robustly routed to the PM), is highly susceptible to single-point mutations that result in disease. A single change in net charge is sufficient to tip the balance in favor of the endoplasmic reticulum and diminish GnRHR available at the PM. The apparent paradox that results from observing convergent pressure for evolution of a receptor that is both inefficiently produced and highly susceptible to mutational disease suggests that this approach must offer a strong advantage. This review focuses on the evolved mechanisms and considers that this is an underappreciated mechanism by which the cell controls functional levels of receptors and other proteins at the posttranslational level.
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PHARMACOPERONES AND RECEPTOR RESCUE
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A GREAT DEAL of attention is now focused on the means by which proteins move from their site of synthesis in the endoplasmic reticulum (ER) to the plasma membrane (PM). This appears to be a highly regulated process and one that is a potential therapeutic target. Proteins frequently undergo complex processing whereby they are folded and concurrently assessed for overall quality by a process collectively referenced as the cellular "quality control system." Components of this system include endogenous chaperone proteins that may assist in folding or may recognize defects that cause a protein to be retained in the ER and reprocessed or destroyed completely. The quality control system identifies general motifs indicative of the defective nature of the protein (e.g. exposure of a hydrophobic plate in an aqueous environment). It does not appear to recognize defects that are specifically associated with individual proteins (such as the inability of a particular receptor to recognize its ligand). This led to the understanding that proteins recognized as defective may still retain function (i.e. receptors might still bind ligand, or enzymes might still catalyze reactions), but only be misrouted within the cell because the quality control system considers them defective. Accordingly, the opportunity presented itself to rescue such mutants and restore them to function (1, 2, 3). This can be accomplished by pharmacological chaperones (pharmacoperones, small molecules that enter the cell and correct folding errors). These molecules act as folding templates and allow mutants to fold correctly and escape the quality control system of the cell. The use of pharmacoperones and other approaches have revealed that virtually all reported point mutations of the GnRH receptor (GnRHR), isolated from patients with hypogonadotropic hypogonadism (HH), appear to be misfolded proteins that are retained by the cellular quality control system and degraded, rather than transferred to the plasma membrane (1, 2, 3). In the presence of these agents, the mutants escape detection or retention and are trafficked to the plasma membrane.
The more recent observation that pharmacoperones could increase the plasma membrane expression (i.e. Bmax) of wild-type (WT) (i.e. nonmutant proteins) led to the understanding that a large percentage of WT proteins may be misfolded themselves and retained in the ER. The recognition that this event is species specific now presents the view that control of the percentage of synthesized receptors that traffic to the plasma membrane has evolved.
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DOES FORM FOLLOW FUNCTION?
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The GnRHR is the analog to digital converter that integrates the neural system of the hypothalamus with the pituitary endocrine system. Although it recognizes the same ligand in most mammals, this receptor must also serve the different regulatory styles of reproduction in dogs (which show pseudopregnancy), mice (very short cycling animals), guinea pigs (unusual rodents with a primate-like long luteal phase), and humans (strongly susceptible to environmental influences). Even so, the homology of the GnRHR to humans is high: 92% (dog), 89% (mice), and 85% (guinea pigs).
The remarkable level of homology is maintained in the face of substantial differences in reproductive styles that require varying investments of metabolic energy per offspring (or, in the case of eggs, potential offspring). Fish produce many eggs and only small percentages actually survive to maturity, whereas mammals, in particular primates, have a much larger metabolic and time commitment (gestation) to each offspring. The immediate corollary of the higher cost of producing offspring is that there is strong selective advantage in controlling this process more closely.
It is hard to imagine that the decapeptide ligand (GnRH) is the driving force to maintain receptor homology because it would not be expected to bind at much more than a few points. Likewise, conservation of structure is unlikely to come from the site of interaction with effector G protein (because this is on the inside of the cell). Conceivably, some of the structure is needed to maintain the characteristic stability of the heptahelical G protein-coupled receptor (GPCR) construct, but Nature herself shows that there are lots of very different ways to achieve that result, given the nearly 1000 GPCRs believed to reside in the human genome.
We were left wondering whether the GnRHR, one of the smallest members of the GPCR superfamily, at 328 amino acids in most mammals (327 in rats and mice), might actually be a model laboratory with which to examine the way receptors are designed for function. With a relatively short amino terminus and no intracellular carboxyl terminus (it virtually truncates in the plasma membrane), the GnRHR is close to the smallest size that can sustain the heptahelical shape characteristic of its superfamily. Because of the small size, one might expect disproportionately large influences of single mutations.
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RATS AND MICE: A MODEST DIFFERENCE LEADS TO A MAJOR REGULATORY CHANGE
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In humans we noticed that dimerization (or oligomerization) of the GnRHRs plays a significant role in movement of the GnRHR from the site of synthesis in the cell to the plasma membrane. We know this because, when mutant and WT receptors are coexpressed, the mutant is both retained itself and causes the retention of the WT (3). The use of confocal microscopy (4) revealed that this dominant-negative (DN) effect of the mutant on the WT appears to result from a physical interaction between these two moieties. In extending these findings to mutants of the rat and mouse GnRHR, we noted that these have very different DN (4, 5) actions on the WT receptor (6), even though the homology between these is 96%. Newly synthesized rat WT retains the ability to oligomerize (because human and mouse mutants exert a DN effect on rat WT sequence) but, unlike human or mouse, escapes the DN effect of GnRHR mutants because rat GnRHR mutants route to the plasma membrane with much higher efficiency than mouse or human mutants.
Figuring out the important structural difference was a straightforward exercise, because there were only four nonconservative (or semiconservative) differences. This made it possible to make all the combinations in between (6). In the end, it came down to a single amino acid change, the substitution of a Gly216 (mouse) for a Ser216 (rat), a net difference of –CH2O out of a molecule with 327 amino acids (6). We found it remarkable that such a modest change could have such a large impact on function. The observation that a single nucleotide change results in a major regulatory change is an indication of how small percentage differences in DNA between species may manifest themselves in substantive regulatory differences.
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MUTATIONS IDENTIFIED FROM HH PATIENTS HAVE LESS IMPACT ON TRAFFICKING IN RAT AND MOUSE SEQUENCES
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Suspicious of the impact of routing differences between species, we reconstructed a number of mutations identified from patients with HH in mouse and rat GnRHR sequences (Ref. 6 and Fig. 1
). In the human these changes of single amino acids caused disease because they resulted in misfolding and subsequent identification by the cellular quality control system as being defective. They were retained in the ER for destruction (5). To our surprise, many of these mutations frequently resulted in having very little or no effect in rat or mouse sequences.
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Fig. 1. Mutations of the Human GnRHR Identified from Patients with HH Were Reconstructed in Templates of Human, Mouse, and Rat GnRHR
Plasmids containing the indicated sequences were transfected into host Cos-7 cells as previously described (6 ) and expressed in the presence or absence of pharmacoperone "IN3" (Merck & Co., Inc., Rahway, NJ). Note that many human mutants can be rescued by this pharmacoperone, which corrects the folding errors associated with mutations. In addition, this approach increases the expression of human, but not mouse or rat WT GnRHR. Homologous mutants prepared in the mouse or rat template have less impact on routing of functional receptor to the plasma membrane than those prepared in the human template, because the GnRHR in these species routes with higher efficiency to the PM. This image was modified from a prior publication (6 ) where experimental details can be found. DMSO, Dimethylsulfoxide; IP, inositol phophates.
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Because pharmacological chaperones could rescue them, we knew that the effect of these mutations was to cause protein misfolding and a resultant loss of the ability to move from the site of synthesis to the plasma membrane. It was not a loss of the ability to bind ligand or interact with the effector. The rescued proteins could function identically to the wild type molecules.
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PHARMACOPERONES REVEAL THAT A LARGE PERCENTAGE OF THE HUMAN, BUT NOT RAT, GnRHR IS RETAINED AND NEVER ARRIVES AT THE PLASMA MEMBRANE
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The further observation that pharmacoperones increased the plasma membrane expression of the WT human GnRHR itself, but not the rat counterpart, meant that the human protein was only partly transferred to the plasma membrane and the remainder was apparently being wasted.
Because Nature is not usually wasteful without a very good reason, we figured that there had to be one! Moreover, the observation that the human molecule was so susceptible to mutations that alterations of single charges in the receptor structure supported the view that the human receptor was very precariously balanced between retention in the ER and routing to the plasma membrane, something that was not seen in rats or mice.
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PART OF A BIGGER PICTURE
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Standing back and looking at the broader evolutionary pattern, we noticed that (unlike mammals) fish, reptile, and bird GnRHRs have an extended carboxyl tail that prolonged the presence of the receptor on the plasma membrane (7). Among mammals (other than rats and mice), we observed the insertion of an amino acid, Glu191 in most preprimates and Lys191 among primates, progressively resulted in diminished expression at the plasma membrane. Replacement of the Lys191 normally in humans with Glu191 showed that this amino acid was slightly less effective than the Lys in inhibiting movement to the plasma membrane. Nature is actually evolving a progressively less efficiently expressed receptor by a convergent process and several means.
We became interested in the molecular mechanism by which the human GnRHR was becoming inefficiently expressed, compared with the rat GnRHR. How could the cell program the efficiency of expression?
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BRIDGES AND RECEPTOR FOLDING
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A big break came from performing a comparative study between the human and the rat GnRHR as we examined the two Cys bridges that form in the molecule (see schematic of the human GnRHR, Fig. 2 and Ref. 8). One connecting the first and second extracellular loops (ECL1 and ECL2; shown as purple) was so essential for activity that, in rats, mice, and humans, conversion of the Cys at either end to Ala resulted in loss of activity at the plasma membrane Cys bridges at homologous positions are found in almost all GPCRs known, and so this observation was not too surprising, because the bridge appears to be a structural feature associated with the fundamental stability of the GPCR motif.
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Fig. 2. Model of the Human GnRHR Showing Disease-Causing Mutations Reported in the Literature
Circles represent amino acids; those colored yellow are rescuable with pharmacoperones, suggesting that the mutation results in a correctable misfolding/misrouting problem. Circles colored orange are in a "zone of death" (orange rectangle) and cannot be rescued; this is due to extremely unfavorable mutations (both Ser  Arg) that cause gross misfolding by preventing the formation of the Cys14–Cys200 bridge (green). For amino acids represented by the circles colored in blue, there has not been any attempt at rescue. For reference, Lys191, a residue that destabilizes formation of this bridge, is shown in red. This residue is present in all primates cloned to date, but is frequently replaced by Glu191 in other mammals. At the time this review is being written, there are 18 mutants known to us to cause isolated HH. Of these, two are missing large sequences: one being a truncation of all amino acids between 314 and the amino-terminal amino acid 328 (shown by gray lettering) and the other, a deletion mutant is missing exon 2 (data not shown). It is reasonable to assume that such a large sequence omission would have a dramatic effect on the receptor structure. The remaining mutations are subtler, involving only a single amino acid. Of these, three involve loss (two occurrences, blue lettering) or gain (one occurrence, blue lettering) of a Cys residue, an amino acid known to form bridges associated with the formation of third-order structure of proteins. Disruption of required bridges or formation of inappropriate bridges would, also, be significantly disruptive to the structure of the protein. One of the most recently reported mutations (orange lettering) is associated with the loss of a Pro at amino acid 320, which is replaced by Leu. Because the peptide backbone of Pro is constrained in a ring structure, occurrence of this amino acid is associated with a forced turn in the protein sequence. The remainder, 12 mutants are, surprisingly, modest changes in a single charge (yellow lettering). Ten of these mutations involve Lys (three occurrences, positively charged), Arg (six occurrences, positively charged amino acids) or Asp (negatively charged, one occurrence). Introduction of even minor charge modifications appears sufficient to create altered folding. Of interest, none of the reported mutations are of a conservative nature in which Ala replaces a Gly or Thr replaces a serine: in each case adding a single carbon without modifying the net charge. Curiously, there are no examples of simple hydrophobic for hydrophobic exchanges (Val for Ala, for example), positive for positive (Lys for Arg) exchanges, or negative for negative (Asp for Glu) exchanges. Such exchanges may occur, of course, but be clinically silent or, in the alternative, the phenotype may not survive.
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The other bridge, connecting the amino terminus with the second ECL (shown as green), is more interesting. First, this bridge is less common in GPCRs; and, second, it appeared requisite in the human and less important in the mouse or rat GnRHR. Mutations of Cys Ala in the rat or mouse had only modest effects on receptor expression at the plasma membrane, whereas in the human it was an absolute requirement.
There were three additional observations that were important. First, a pharmacoperone could rescue the human receptor with Cys14Ala or Cys200Ala, suggesting that the bridge was needed for proper folding. Second, the deletion of Lys191 in the human obviated the need to form the bridge, suggesting that this residue was destabilizing the structure required for formation of the bridge. Third, preparation of the rat homolog in which Lys191 was inserted did not result in destabilization of the rodent receptor. This simply meant there was a more complex difference between the rat and the human that was required for the destabilizing effect of the Lys191.
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HOW THE RAT GnRHR IS DIFFERENT THAN THE HUMAN GnRHR
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The identification of the important differences between the rat and the human GnRHR was a more daunting task because there were 39 amino acid differences between the rat and human GnRHR sequence and a seemingly endless number of mutants to explore all the combinations.
We approached this problem by locating the thermodynamically unfavored changes (8), figuring that these might be the most important. Interestingly there were only three, and these were located in close physical proximity to the Lys191 and to the Cys14–Cys200 bridge. It was also interesting that these all involved the loss or gain of a Ser or Pro, both amino acids associated with introducing a bend in the protein backbone and setting the alignment between the second ECL and the amino terminus.
The rest of the motif was identified by making guesses about the physical relation between amino acids in the three-dimensional state. We used this information to create human receptors that were modified to be rat like at four residues. These expressed at the higher levels associated with rat receptor and lacked the requirement for the Cys14–Cys200 bridge—another feature of the rat GnRHR.
The spatial alignment was quite important because the two Cys residues had to be within about the size of one water molecule in order for the bridge to form. When the bridge forms, the human GnRHR is recognized by the cellular quality control system as correctly folded. When it does not form, it is viewed as defective and retained (then presumably destroyed) in the ER. The cell is exploiting this approach as a means of controlling routing in normal function of healthy cells using this technique to control the efficiency of expression of the protein at the plasma membrane—but why? Why waste receptor? Why construct a receptor that is so delicately balanced between the plasma membrane and the ER that a single charge change results in disease?
Indeed, among receptor mutants associated with HH, 12 of 18 are associated with changes in the charge of single amino acids. The rest are insertion or removal of prolines, that forcibly bend the receptor structure or the insertion or removal of cysteines that result in loss or gain of Cys bridges.
A couple of other things attracted our attention. First, the conversion of the Gly216 (mouse) to Ser216 (rat) that altered the DN effect in these species was a mutation that resulted in torsion of the ECL2 and is, accordingly, in a position that reasonably might impact the relation between the Cys14 and Cys200, attaching the amino terminus to the ECL2. Second, mutants Ser168Arg and Ser217Arg are in a previously reported "zone of death" (1) and cannot be rescued by any of several different chemical classes (indoles, quinolones, and erythromycin macrolides) of pharmacoperones that successfully rescued other mutants—a rare circumstance, because the vast majority of mutants are rescuable by all classes (9).
We had initially considered that these sites might be unrescuable because they were important for the ligand-receptor interactions. We now realize that there is a different explanation. This observation and the physical relation between transmembrane segment 4 and transmembrane segment 5 to ECL2 make it attractive to consider that (charge altering) mutations in these two residues exert their influence by regulating the position of ECL2 and the intimacy of Cys14 and Cys200. Due to charge considerations, the thermodynamically unfavored exchange of Ser and Arg likely moves the ECL2 into a position from which the formation of a Cys bridge is improbable and the mutant never passes the cellular quality control system even in the presence of pharmacoperones.
Because the rat lacks the extra amino acid at position 191, the homologous position of amino acid 217 in the human is 216 in the rat—the very same position that distinguished the rat from the mouse by interconversion of a Gly (mouse) to Ser (rat). The amino acids selected are interesting, as suggested above. Ser, with a slightly polar nature, small size, and propensity of the side-chain hydroxyl oxygen to H bond with the protein backbone, also causes it to be found in association with tight turns of the protein structure. Gly, on the other hand, is very flexible.
In considering the molecule as a whole, the rat human modifications associated with orientation of ECL2 (positions 7, 168, 189, and 202/203) all involve the gain or loss of Pro or Ser. Pro forms a five-membered nitrogen-containing ring, a feature that causes it to be found in very tight turns in protein structures (i.e. where the polypeptide chain must change direction). Clearly Nature has tipped her hand: the peptide backbone is being bent to control the relation between the Cys14 and Cys200 and to control the probability of formation of the bridge.
Toleration, let alone strong and convergent evolutionary pressure for such mutational liability, along with the burden of inefficient function, suggests that this posttranslational regulation is extremely important in advanced mammals. It provides a mechanism by which proteins, through interactions with the quality control system, can rapidly respond to demand without protein synthesis.
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SO WHY IS THIS HAPPENING?
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It may go back to form following function. Having extra receptors that can be called upon to be available in times of need (i.e. through cyclicity) may be very important. Armed with this idea, we examined the outliers—animals whose sequences appeared odd compared with others. We found several, and all of these have marked differences in their reproductive patterns when compared with their evolutionary close relations. Of rodents, animals with large litters, only the guinea pig is known to have added an amino acid (Glu) at position 191 of the GnRHR. Interestingly, the guinea pig, a hystricomorph that diverged very early in rodent evolution, has a long luteal phase (a primate characteristic). Most nonrodent mammals, such as cows, sheep, pigs, dogs, and horses, also contain Glu191, suggesting that the loss of an amino acid in the homologous position is a specialization associated with very short reproductive cycles in rats and mice. Unlike all other reported mammalian sequences, the opossum (a nonplacental mammal that places fetuses in a marsupium) has an uncharged, racemic Gly191 that may reflect the early divergence of this group and specializations needed for this relatively unique form of reproduction compared with other mammals.
Is this a unique exercise of the human GnRHR? We think this event is more generally applicable in light of recent reports of other receptors that are also inefficiently expressed (10, 11, 12, 13, 14, 15). It will be necessary to determine whether other proteins follow the same regulatory mechanism. Candidate proteins are likely to 1) show sensitivity to single-point mutations (naturally occurring or created) in which net charge is added or altered and 2) such mutations will be distributed generally throughout the molecule, as is the case with the GnRHR. Application of these criteria may enable selection of candidate molecules for subsequent study.
Presently, there are no other GPCRs for which this evolved restriction of plasma membrane expression has been documented. There may be others, of course, but the GnRHR may have provided a unique opportunity for two reasons. First, it is among the smallest of GPCRs (328 amino acids), making preparations of a large number of mutants (nearly 200) needed for this study an achievable goal. Second, the complexity of reproduction (requiring recognition of hormone frequency modulation, tighter control of gonadotropin release, development of two gonadotropins, and reproductive system cyclicity) has evolved dramatically as the investment in creating a single offspring increased. Whether this pattern of regulation extends to other proteins remains at question.
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FOOTNOTES
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This work was supported by National Institutes of Health Grants HD-19899, RR-00163, TW/HD-00668, and HD-18185.
Summary of Disclosures: None.
First Published Online March 23, 2006
Abbreviations: DN, Dominant-negative; ECL, extracellular loop; ER, endoplasmic reticulum; GPCR, G protein-coupled receptor; GnRHR, GnRH receptor; HH, hypogonadotropic hypogonadism; WT, wild type.
Received for publication February 8, 2006.
Accepted for publication March 14, 2006.
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REFERENCES
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- Conn PM, Leaños-Miranda A, Janovick JA 2002 Protein Origami: therapeutic rescue of misfolded gene products. Mol Interv 2:308–316[Abstract/Free Full Text]
- Ulloa-Aguirre A, Janovick JA, Brothers SP, Conn PM 2004 Pharmacological rescue of conformationally-defective proteins. Implications for the treatment of human disease. Traffic 5:821–837[CrossRef][Medline]
- Castro-Fernandez C, Maya-Nunez G, Conn PM 2005 Beyond the signal sequence: protein routing in health and disease. Endocr Rev 26:479–503[Abstract/Free Full Text]
- Leaños-Miranda A, Ulloa-Aguirre A, Ji TH, Janovick JA, Conn PM 2003 Dominant-negative action of disease-causing gonadotropin-releasing hormone receptor (GnRHR) mutants: a trait that potentially coevolved with decreased plasma membrane expression of GnRHR in humans. J Clin Endocrinol Metab 88:3360–3367[Abstract/Free Full Text]
- Brothers SP, Cornea A, Janovick JA, Conn PM 2004 Human ‘loss-of-function’ GnRH receptor mutants retain WT receptors in the ER: basis of the dominant-negative effect. Mol Endocrinol 18:1787–1797[Abstract/Free Full Text]
- Knollman PE, Janovick JA, Brothers SP, Conn PM 2005 Parallel regulation of membrane trafficking and dominant-negative effects by GnRH receptor mutants. J Biol Chem 280:24506–24514[Abstract/Free Full Text]
- Lin X, Janovick JA, Brothers SP, Blomenröhr J, Bogerd J, Conn PM 1998 Addition of catfish gonadotropin-releasing hormone (GnRH) receptor intracellular carboxyl-terminal rail to rat GnRH receptor alters receptor expression and regulation. Mol Endocrinol 12:161–171[Abstract/Free Full Text]
- Janovick JA, Knollman PE, Brothers SP, Conn PM 2006 Regulation of G protein coupled receptor trafficking by inefficient plasma membrane expression: molecular basis of an evolved strategy. J Biol Chem 281:8417–8425[Abstract/Free Full Text]
- Janovick JA, Goulet M, Bush E, Greer J, Wettlaufer DG, Conn PM 2003 Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther 305:608–614[Abstract/Free Full Text]
- Petäjä-Repo UE, Hogue M, Ghalla S, Laperrière A, Morello JP, Bouvier M 2002 Ligands act as pharmacological chaperones and increase the efficiency of
opioid receptor maturation. EMBO J 21:1628–1637[CrossRef][Medline] - Vandenberghe W, Nicoll RA, Bredt DS 2005 Interaction with the unfolded protein response reveals role for stargazin in biosynthetic AMPA receptor transport. J Neurosci 25:1095–1102[Abstract/Free Full Text]
- Petrovska R, Kapa I, Klovins J, Schioth HB, Uhlen S 2005 Addition of a signal peptide sequence to the
(1D) adrenoceptor gene increases the density of receptors, as determined by [(3)H]-prazosin binding in the membranes. Br J Pharmacol 144:651–659[CrossRef][Medline] - Uberti MA, Hague C, Oller H, Minneman KP, Hall RA 2004 Heterodimerization with ß-2-adrenergic receptors promotes surface expression and functional activity of -1D-adrenergic receptors. J Pharmacol Exp Ther 313:16–23[Medline]
- Saito H, Kubota M, Roberts RW, Chi Q, Matsunami H 2004 TRP family members induce functional expression of mammalian odorant receptors. Cell 119:679–691[CrossRef][Medline]
- Pietila EM, Tuusa JT, Apaja PM, Aatsinki JT, Hakalahti AE, Rajaniemi HJ, Petaja-Repo UE 2005 Inefficient maturation of the rat luteinizing hormone receptor: a putative way to regulate receptor numbers at the cell surface. J Biol Chem 280:26622–26629[Abstract/Free Full Text]
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ABSTRACT
PHARMACOPERONES AND RECEPTOR...