Molecular neurobiology of dopamine receptor subtypes.
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Amino Acid Sequence↗
Biomedical subjects
L C Mahan
Publications and source records attributed to L C Mahan.
Differential and transient expression of GABAA receptor alpha-subunit mRNAs in the developing rat CNS.
The expression of mRNAs coding for alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of the GABAA neurotransmitter receptor was followed during the development of the rat CNS by in situ hybridization histochemistry. Expression of these subunit mRNAs in tissue sections of embryonic day 15 and 17 (E15, E17) whole rat and in brain at ages greater than E17 to adult were varied, transient, and region specific. Subunit mRNAs first detected at E15 were those coding for the alpha 2 and alpha 3 subunits. At E17, alpha 2, alpha 3, and alpha 5 mRNAs were present in abundance in numerous areas in the CNS, with lower but significant amounts of alpha 6 being present in the cortical neuroepithelial layers. However, alpha 6 subunit mRNA expression in the cortex declined until little or no alpha 6 mRNA was detected at E19. alpha 1 subunit mRNA first appeared at E19 in the cortex, followed by expression in the hippocampus by postnatal 5 (PN5). Particularly high expression of alpha 2 and alpha 5 subunit mRNAs was detected throughout the developing CNS, but they were most abundant in the olfactory bulb neurons. The high levels of alpha 2 and alpha 5 subunit mRNAs began to decline around PN5 to the amounts observed in adult. These results demonstrate that numerous GABAA receptor alpha-subunits are expressed before birth in a region- and age-specific manner. This complex and varied expression supports the hypothesis that GABA may play a role in cellular and synaptic differentiation.
Animals↗
Molecular cloning and expression of a pituitary somatostatin receptor with preferential affinity for somatostatin-28.
Using the polymerase chain reaction technique with degenerative primers, we obtained from a rat pituitary cDNA library a cDNA fragment, rAP236, that exhibited considerable homology to known receptors that belong to the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. Oligonucleotides to this fragment were used as probes to obtain a full-length cDNA from the rat pituitary cDNA library. This clone, rAP6-26, encoded a 383-amino acid protein with seven putative transmembrane domains that are characteristic of G protein-coupled receptors. The predicted amino acid sequence of the rAP6-26 cDNA exhibits 56-66% homology to recently cloned somatostatin (SRIF) receptors. Membranes prepared from COS-7 cells transfected with the rAP6-26 cDNA showed specific binding of 125I-Tyr11-SRIF, thus identifying the cDNA clone as a novel SRIF receptor. Radioligand binding competition analysis using somatostatin-28 (SRIF-28) and a number of cyclic SRIF analogs revealed that SRIF-28 was the most potent competitor of 125I-Tyr11-SRIF binding, with a approximately 30-fold greater affinity for the receptor than that of SRIF. In addition, binding of 125I-Tyr11-SRIF was markedly reduced in the presence of Na+ ions and GTP, indicating coupling of rAP6-26 receptors to inhibitory G proteins in COS-7 membranes. In adenylyl cyclase assays, forskolin-induced cAMP accumulation was inhibited by SRIF and SRIF-28, thus confirming that the rAP6-26 cDNA encodes a functional receptor protein. By Northern blot analysis, a approximately 2.6 kilobase mRNA encoding the receptor was present in the pituitary but not in the liver, small intestine, kidney, pancreas, cerebellum, or cortex. Lack of receptor mRNA expression in the brain was confirmed by in situ hybridization histochemical studies. Thus, we report the cloning of a novel rat pituitary SRIF receptor, termed SSTR4, that has marked preferential affinity for SRIF-28 and is linked to inhibition of adenylyl cyclase.
Amino Acid Sequence↗
GABAA receptors containing alpha 1 and beta 2 subunits are mainly localized on neurons in the ventral pallidum.
The gamma-aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is important in the regulation of locomotion. Thus, stimulation and inhibition of GABAA receptors in the VP can alter locomotor activity. To determine whether the GABAA receptors are located presynaptically on accumbens efferents to the VP or postsynaptically on neurons intrinsic to the VP two experiments were performed. In the first, quinolinic acid lesions of the nucleus accumbens did not alter [3H]muscimol binding in the VP, while lesions in the VP significantly reduced (60-80%) binding as measured by light microscopic receptor autoradiography. In the second experiment, in situ hybridization with oligonucleotide probes for mRNAs of the alpha 1 and beta 2 subunits of the GABAA receptor was examined in the nucleus accumbens and VP. No mRNA for either subunit was observed in the nucleus accumbens, although many positively labeled neurons were present within the VP. By contrast, a moderate to high density of cells in both the nucleus accumbens and VP contained mRNA for glutamic acid decarboxylase. These data argue that the majority of GABAA receptors in the VP are not located presynaptically on axonal terminals originating from neurons in the nucleus accumbens.
Animals↗
Oligonucleotides antisense to the interleukin 1 receptor mRNA block the effects of interleukin 1 in cultured murine and human fibroblasts and in mice.
Phosphodiester and phosphorothioate oligodeoxynucleotides (18 mers) were constructed antisense to sequences of the recently cloned murine and human IL-1 receptors. Murine antisense oligonucleotides inhibited IL-1-stimulated PGE2 synthesis by murine fibroblasts in culture in a time (days) and concentration-dependent (3 microM-30 microM) fashion. Murine sense oligonucleotide and an oligonucleotide antisense to human IL-1 receptor were without effect. Moreover, murine antisense oligonucleotides did not affect tumor necrosis factor- or bradykinin-stimulated PGE2 synthesis by murine fibroblasts. Similarly, antisense oligonucleotides to the human, but not the murine, IL-1 receptor inhibited IL-1-stimulated PGE2 synthesis by cultured human fibroblasts. The attenuation of the cellular response to IL-1 caused by the antisense oligonucleotides correlated with a loss in cell surface receptors for IL-1, without any change in the number of bradykinin receptors on these cells. When antisense oligonucleotides were encapsulated in liposomes, they blocked completely the appearance of newly synthesized IL-1 receptors and IL-1-stimulated PGE2 synthesis. In mice, subcutaneous injection with an oligonucleotide antisense to the murine IL-1 receptor markedly inhibited the infiltration of neutrophils in response to subsequent injection of IL-1. These data suggest that antisense oligodeoxynucleotides may share a role in the design of antiinflammatory therapeutics.
Animals↗
Transfected D2 dopamine receptors mediate the potentiation of arachidonic acid release in Chinese hamster ovary cells.
A rat D2L dopamine receptor, a splice variant of the D2 receptor, has recently been cloned. When transfected into and stably expressed in Chinese hamster ovary cells, these receptors mediate the inhibition of both basal and forskolin-stimulated cAMP production, as previously described. We examined what role this receptor might play in the production of the second messenger arachidonic acid. The calcium ionophore A23187 stimulated the release of arachidonic acid, and this release of arachidonic acid was potentiated by dopamine in a concentration-dependent manner. Dopamine alone, however, had no effect on arachidonic acid release. Quinpirole, a D2-selective agonist, augmented A23187-stimulated arachidonic acid release, and sulpiride, a D2-selective antagonist, blocked this augmentation. cAMP analogs and agents that activate adenylyl cyclase were utilized in an attempt to overcome this dopamine effect. Forskolin, prostaglandin E2, dibutyryl-cAMP, 8-(4-chlorophenylthio)-cAMP, and pertussis toxin all had no appreciable effect on either A23187-stimulated arachidonic acid release or the dopamine enhancement. Inhibition of protein kinase C using long term phorbol ester desensitization and pharmacological inhibitors diminished the dopamine potentiation of arachidonic acid release. These results suggest that the D2 receptor may be increasing the release of arachidonic acid by a mechanism involving protein kinase C but independent of the D2 receptor's inhibition of adenylyl cyclase.
Adenylate Cyclase Toxin↗
Cloning and expression of an A1 adenosine receptor from rat brain.
We have used the polymerase chain reaction technique to selectively amplify guanine nucleotide-binding regulatory protein (G protein)-coupled receptor cDNA sequences from rat striatal mRNA, using sets of highly degenerate primers derived from transmembrane sequences of previously cloned G protein-coupled receptors. A novel cDNA fragment was identified, which exhibits considerable homology to various members of the G protein-coupled receptor family. This fragment was used to isolate a full-length cDNA from a rat striatal library. A 2.2-kilobase clone was obtained that encodes a protein of 326 amino acids with seven transmembrane domains, as predicted by hydropathy analysis. Stably transfected mouse A9-L cells and Chinese hamster ovary cells that expressed mRNA for this clone were screened with putative receptor ligands. Saturable and specific binding sites for the A1 adenosine antagonist [3H]-1,3-dipropyl-8-cyclopentylxanthine were identified on membranes from transfected cells. The rank order of potency and affinities of various adenosine agonist and antagonist ligands confirmed the identity of this cDNA clone as an A1 adenosine receptor. The high affinity binding of A1 adenosine agonists was shown to be sensitive to the nonhydrolyzable GTP analog guanylyl-5'-imidodiphosphate. In adenylyl cyclase assays, adenosine agonists inhibited forskolin-stimulated cAMP production by greater than 50%, in a pharmacologically specific fashion. Northern blot and in situ hybridization analyses of receptor mRNA in brain tissues revealed two transcripts of 5.6 and 3.1 kilobases, both of which were abundant in cortex, cerebellum, hippocampus, and thalamus, with lower levels in olfactory bulb, striatum, mesencephalon, and retina. These regional distribution data are in good agreement with previous receptor autoradiographic studies involving the A1 adenosine receptor. We conclude that we have cloned a cDNA encoding an A1 adenosine receptor linked to the inhibition of adenylyl cyclase activity.
Amino Acid Sequence↗
D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.
The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Molecular cloning and expression of a D1 dopamine receptor linked to adenylyl cyclase activation.
In order to clone the D1 dopamine receptor linked to adenylyl cyclase activation, the polymerase chain reaction was used with highly degenerate primers to selectively amplify a cDNA sequence from NS20Y neuroblastoma cell mRNA. This amplification produced a cDNA fragment exhibiting considerable sequence homology to guanine nucleotide-binding (G)-protein-coupled receptors that have been cloned previously. To characterize this cDNA further, a full-length clone was isolated from a rat striatal library by using the cDNA fragment as a probe. Sequence analysis of this cDNA clone indicated that it is indeed a member of the G-protein-coupled receptor family and exhibits greatest homology with the previously cloned catecholamine receptors. Northern blot analysis of various neural tissues revealed a transcript of approximately 4 kb that was predominantly located in the striatum with lesser amounts in the cortex and retina. In contrast, no mRNA was detected in the cerebellum, hippocampus, olfactory bulb, mesencephalon, or pituitary. In situ hybridization analysis also revealed a high abundance of mRNA in the striatum as well as in the olfactory tubercle. To establish the identity of this cDNA, we performed transient expression experiments in COS-7 cells. [3H]SCH-23390, a D1-selective radioligand, exhibited specific, saturable binding only in cells that were transfected with this cDNA. Competition binding analysis with a variety of dopaminergic ligands demonstrated a D1 dopaminergic pharmacology. In addition, dopamine as well as other D1-selective agonists stimulated cAMP accumulation in transfected COS-7 cells. We conclude that we have cloned a cDNA encoding the D1 dopamine receptor linked to the activation of adenylyl cyclase activity.
Adenylyl Cyclases↗
Expression of striatal D1 dopamine receptors coupled to inositol phosphate production and Ca2+ mobilization in Xenopus oocytes.
Expression of central nervous system receptors for dopamine was examined by injection of poly(A)+ RNA (mRNA) from rat striatum into oocytes from Xenopus laevis. Electrophysiological measurements in mRNA-injected oocytes indicated that addition of 100 microM dopamine induced an inward current (40-100 nA) that was consistent with the activation of endogenous Ca2(+)-dependent Cl- channels. This current was also elicited by addition of the selective D1 agonist SKF 38393 but not by the selective D2 agonist quinpirole. Prior addition of the dopaminergic antagonist cis-piflutixol completely abolished dopamine-induced currents but had no effect on currents produced by serotonin. Using 45Ca2+ efflux assays, addition of 100 microM dopamine to injected oocytes stimulated efflux 2- to 3-fold. This increase was mimicked by SKF 38393 and was blocked by the D1-selective antagonist (+)SCH 23390 but not by the D2-selective antagonist domperidone. No increase in 45Ca2+ efflux was seen with 100 microM quinpirole. Size fractionation of striatal mRNA yielded a single peak (2.5-3.0 kilobases) of D1 receptor-mediated 45Ca2+ efflux activity in injected oocytes. In addition, dopamine stimulation of oocytes injected with peak fractions and prelabeled with myo-[3H]inositol caused a 3-fold increase in [3H]inositol 1,4,5-triphosphate [( 3H]InsP3) formation. No effect on [3H]InsP3 production or 45Ca2+ efflux was observed, however, in injected oocytes incubated with 1 mM N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate. Thus, in addition to D1 receptors that stimulate adenylyl cyclase, rat striatum contains D1 receptors that can couple to InsP3 formation and mobilization of intracellular Ca2+.
Animals↗
Beta-adrenoceptor metabolism in wild-type, Gs, and protein kinase A-variant S49 cells.
To determine the role of the stimulatory guanine nucleotide-binding protein, Gs, and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase in the basal metabolism of beta-adrenergic receptors in S49 lymphoma cells, we measured the return of receptor number and function after irreversible blockade of receptors. After inactivation of receptors with the irreversible ligand N8-(bromoacetyl)-N'-[3-(4-indolyoxy)-2-hydroxypropyl]-(2)-1,8-diam ino-p- methane (BIM), beta-adrenergic receptors (defined as [125I]iodocyanopindolol binding sites) reappeared in a biphasic manner, the faster phase having a half-time (t 1/2) of 3-8 h (approximately 50% of the sites) and the slower phase greater than 40 h. Although the slow phase is not readily explained, recovery of binding sites during the first 10 h matched recovery of receptor function after BIM treatment (as measured by stimulation of cAMP accumulation) and recovery of receptor sites after downregulation induced by the agonist isoproterenol. Thus quantifying receptor recovery during the first 10 h after BIM treatment appears to be a reasonable method for examining basal receptor metabolism in S49 cells. Measured in this way, metabolism of beta-adrenergic receptors is very similar in wild-type S49 and the following variant clones: cyc- (absent Gs alpha), UNC and H21a (defective Gs alpha), and kin- (lacking cAMP-dependent protein kinase activity). Although previous data have demonstrated that agonist-promoted downregulation of beta-adrenergic receptors requires functional receptor-Gs coupling, the current data suggest that neither Gs nor cAMP-dependent protein kinase activity plays an important role in the regulation of basal metabolism of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Functional expression of B2 bradykinin receptors from Balb/c cell mRNA in Xenopus oocytes.
The murine BALB/c 3T3 fibroblast clone SV-T2 (3T3 cells) expresses receptors for the nonapeptide bradykinin. In these cells, bradykinin stimulates both inositol phosphate (InsP) formation and arachidonic acid release by independently activating phospholipase C and phospholipase A2, respectively. These actions of bradykinin are mediated by a receptor(s) coupled to pertussis toxin-insensitive guanine nucleotide-binding proteins. Bradykinin-stimulated increases in InsP lead to the mobilization of intracellular Ca2+. We examined the expression of 3T3 receptors for bradykinin in oocytes from Xenopus laevis, cells capable of in vitro expression of foreign mRNA for receptors coupled to the mobilization of Ca2+. Poly(A)+ mRNA was prepared from 3T3 cells and expression of receptors for bradykinin was demonstrated by agonist-mediated stimulation of 45Ca2+ efflux from oocytes injected with 50 ng of poly(A)+ RNA. Bradykinin-stimulated efflux of 45Ca2+ was dose dependent (EC50 = 15 nM) and blocked by the specific mixed B1,B2 bradykinin antagonist NPC 567 but not by the B1 antagonist desArg9[Leu8]bradykinin. Size fractionation of 3T3 poly(A)+ RNA on a sucrose gradient demonstrated a single peak of bradykinin-stimulated 45Ca2+ efflux, with an approximate mRNA size of 4.5 kilobases. Bradykinin-stimulated 45Ca2+ efflux in size-fractionated mRNA was clearly separable from response to [Arg]vasopressin at another receptor linked to InsP formation and Ca2+ mobilization in 3T3 cells.
Animals↗
Pharmacological characterization and region-specific expression in brain of the beta 2- and beta 3-subunits of the rat GABAA receptor.
The cDNA for a third beta-subunit of the rat GABAA receptor has been cloned using another beta-subunit, which we had previously cloned [(1989) FEBS Lett. 246, 145-148], as a probe. The approximately 8-kb cDNA for this beta-subunit (termed beta 2) encodes a protein of 474 amino acid residues that shares approximately 80% sequence identity with the rat and bovine beta 1- and beta 3-subunits. Coexpression of the cloned beta-subunit cDNA with the alpha 1-subunit cDNA of the rat GABAA receptor in Xenopus oocytes produced a functional receptor and Cl- channel with pharmacological characteristics of a GABAA receptor. In contrast to interchanging alpha-subunits [(1988) Nature 335, 76-79], exchange of beta 2- or beta 3-subunits in an alpha 1/beta receptor complex did not markedly alter the pharmacological properties of expressed receptors. In situ hybridization histochemistry with synthetic subunit-specific oligo-deoxynucleotide probes revealed a region-specific expression of alpha 1-, beta 2- and beta 3-subunit mRNAs in the rat central nervous system. These observations provide an additional molecular basis for the functional heterogeneity in the GABAA receptor complex.
Animals↗
Multiple GABAA receptor alpha subunit mRNAs revealed by developmental and regional expression in rat, chicken and human brain.
GABAA receptor alpha subunit transcripts were detected by Northern analysis of rat, chicken and human brain mRNA using a series of 32P-labelled antisense RNA probes derived from human alpha 1 subunit cDNAs. These alpha subunit mRNAs differ in their distribution among various brain regions in the rat and at least one species is detected primarily in fetal brain. GABAA receptor alpha 1 subunit probes encoding the putative extracellular domain detect at least five alpha subunit transcripts in rat brain, whereas probes encoding the putative intracellular domain detect only two mRNAs. These data suggest the presence in brain of multiple GABAA receptor alpha subunits having homologous extracellular domains and whose expression is regionally and developmentally regulated. These alpha subunit transcripts may encode proteins that comprise GABAA isoreceptors differing in their pharmacological and physiological properties.
Animals↗
Cloning and expression of a novel rat GABAA receptor.
Two full-length cDNA clones encoding alpha- and beta-subunits of a GABAA receptor have been isolated from a rat cerebral cortex cDNA library. The mature alpha-subunit protein consists of 428 amino acids with a calculated Mr of 48,680. This protein is highly homologous (approximately 99% amino acid identity) with the bovine brain alpha 1-subunit receptor [(1988) Nature 335, 76-79]. The mature rat beta-subunit receptor is a 448 amino acid polypeptide and shares approximately 80% amino acid identity with the previously characterized bovine GABAA receptor beta-subunit [(1987) Nature 328, 221-227]. Co-expression of the cloned DNA in Xenopus oocytes produces a functional receptor and ion channel with pharmacological characteristics of a GABAA receptor. GABAA alpha- and beta-subunit mRNA is detectable in the cortex, cerebellum and hippocampus.
Amino Acid Sequence↗
Certain beta-blockers can decrease beta-adrenergic receptor number: II. Down-regulation of receptor number by alprenolol and propranolol in cultured lymphoma and muscle cells.
We have used two different cultured cell lines--S49 lymphoma cells and BC3H-1 muscle cells--to examine the regulation of beta-adrenergic receptors by receptor antagonists. Rather than an increase ("up-regulation") of receptor number that such antagonists often produce, we found that certain beta-blockers elicit a decrease ("down-regulation") of beta-adrenergic receptors. Alprenolol and propranolol, but not sotalol or ICI 118,551, at concentrations of 10-100 nM down-regulated beta-adrenergic receptors 20-70% following 16-20 hours of treatment of S49 or BC3H-1 cells. Several observations suggest that this phenomenon depends upon beta-receptor interaction, including stereoselectivity [(-)-enantiomers more potent than (+)-enantiomers], blockade of the effect by ICI 118,551, absence of down-regulation of alpha-adrenergic receptors in BC3H-1 cells, and lack of a decrease in beta-adrenergic receptor-independent (forskolin-stimulated) cyclic AMP accumulation in S49 cells. The possibility of retained antagonist interfering with receptor measurement was precluded by the fact that the antagonist-induced decrease in receptor number required several hours incubation and occurred without a prominent change in receptor affinity. The ability of the beta-blockers to elicit down-regulation did not correlate with hydrophobicity of the drugs. Antagonist-induced down regulation of beta-adrenergic receptors did not occur in S49 lymphoma cells that lack the alpha-subunit of Gs, the guanine nucleotide-binding regulatory protein, thus implying a requirement for receptor-alpha s interaction in eliciting beta-receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Translocation of protein kinase C in anterior pituitary tumor cells.
Previous studies have shown that phorbol esters and lithium each stimulate the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary tumor cell line AtT20/D16-16. Pretreatment with either lithium or phorbol ester desensitizes the cells to subsequent stimulation by phorbol ester. An early consequence of phorbol ester action in other systems is the translocation of protein kinase C from cytosol to membranes. We have assayed protein kinase C activity in cytosol and membranes of AtT20 cells after treatment with phorbol dibutyrate, lithium, or other agents that stimulate secretion of ACTH in these cells. Phorbol dibutyrate clearly induced translocation of protein kinase C, but lithium treatment did not cause translocation itself, nor did pretreatment with lithium affect the translocation induced by phorbol dibutyrate. These results are consistent with a role for translocation of protein kinase C in the stimulatory and desensitizing effects of phorbol esters but fail to implicate translocation in the actions of lithium on AtT20 cells.
Adrenocorticotropic Hormone↗
Metabolism of alpha- and beta-adrenergic receptors in vitro and in vivo.
Despite considerable evidence that changes in number of adrenergic receptors can occur under various conditions, knowledge of the mechanisms mediating these changes is still rudimentary. As discussed, indirect approaches emphasizing the kinetics of receptor turnover have been the principal means of investigation. These indirect methods, which depend on the ability of a radioligand to detect the receptors, are limited by several factors. Even so, the data obtained using indirect approaches, in particular on various model systems in cell culture, lead to several conclusions: Both alpha 1- and beta-adrenergic receptors are metabolized rather slowly in vitro under basal conditions, in the absence of exposure to agonists. Typical half-lives are greater than 20 hr, a turnover that is slower than that of several other classes of neurotransmitter and hormone receptors (9, 10, 12, 16). Moreover, alpha 1-adrenergic receptors and beta-adrenergic receptors can have substantially different half-lives, even when expressed on the same cell. In view of the relatively slow rate of disappearance of adrenergic receptors under basal conditions, settings in which receptor number increases are almost certainly to result from increases in one or more of the factors that contribute to the rate of receptor appearance on the plasma membrane. Treatment of cells with agonists markedly shortens the half-life of alpha 1- and beta-adrenergic receptors. This shortened half-life results primarily from an enhanced loss of receptors from the plasma membrane, and not from agonist-induced attenuation of receptor appearance. In fact, data acquired from studies of receptor recovery after agonist-induced down-regulation suggest that rates of receptor reappearance are markedly enhanced through either receptor recycling or an increase in receptor synthesis. Limited studies conducted in vivo yield qualitatively similar results to those observed in in vitro studies of the metabolism of adrenergic receptors. In general, adrenergic receptors in the CNS turn over more slowly than those in peripheral tissues. These conclusions help to highlight the many aspects of metabolism of adrenergic receptors that are as yet unknown, including identification and characterization of the cellular machinery responsible for receptor metabolism, elucidation of the molecular events that control metabolism, and assessment of how drugs and other factors influence these events. Future studies are likely to be based on the development of new methodology with antireceptor antibodies, receptor cDNA's, and improved morphological methods (autoradiography, immunohistochemistry, etc).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗