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The G-Protein-Coupled Receptor Kinases PARK1 and PARK2 Are Widely Distributed at Synapses in Rat Brain

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The G-Protein-Coupled Receptor Kinases PARK1 and PARK2 Are Widely Distributed at Synapses in Rat Brain The Journal of Neuroscience, October 1992, 12(10): 4045-4055 The G-Protein-coupled Receptor Kinases PARK1 and PARK2 Are Widely Distributed at Synapses in Rat Brain Jeffrey L. Arriza,’ Ted M. Dawson,2 Richard B. Simerly,3 Lee J. Martin,’ Marc G. Caron,’ Solomon H. Snyder,’ and Robert J. Lefkowitz’ ‘Departments of Medicine, Cell Biology, and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, ‘Departments of Neuroscience, Neurology, Pathology, Pharmacology and Molecular Sciences, and Psychiatry, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, and 3Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton, Oregon, 97006 The /3-adrenergic receptor kinase (BARK) phosphorylates as a model system (reviewed by Benovic et al., 1988; Hausdorff the agonist-occupied @-adrenergic receptor to promote rapid et al., 1990). In the /3,AR system, agonist binding initiates pro- receptor uncoupling from G,, thereby attenuating adenylyl cessesthat, concurrent with G,-mediated stimulation of adenylyl cyclase activity. BARK-mediated receptor desensitization cyclase, serve to phosphorylate rapidly and thereby desensitize may reflect a general molecular mechanism operative on these receptors. The desensitization.of the &AR by phosphor- many G-protein-coupled receptor systems and, particularly, ylation is reversible (Sibley et al., 1986) presumably through synaptic neurotransmitter receptors. Two distinct cDNAs en- the activity of protein phosphatases.Thus, at synapses,the de- coding @ARK isozymes were isolated from rat brain and se- sensitization of G-protein-coupled receptors by phosphoryla- quenced. The regional and cellular distributions of these two tion may lead, at least transiently, to attenuated neurotrans- gene products, termed PARK1 and BARKS, were determined mission despite persistent stimulation. in brain by in situ hybridization and by immunohistochemistry Distinct pathways for the phosphorylation and desensitiza- at the light and electron microscopic levels. The BARK iso- tion of the /3,AR are mediated by the CAMP-dependent protein zymes were found to be expressed primarily in neurons dis- kinase (PKA), and by the @-adrenergicreceptor kinaseor PARK tributed throughout the CNS. Ultrastructurally, BARK1 and (Hausdorff et al., 1989). PKA is activated by the secondmes- BARK2 immunoreactivities were present both in association sengerproduct of ,&AR stimulation (CAMP) to phosphorylate with postsynaptic densities and, presynaptically, with axon sites on the receptor that directly inhibit receptor-G, coupling terminals. The @ARK isozymes have a regional and subcel- and thereby limit further stimulation of adenylyl cyclase. How- lular distribution consistent with a general role in the de- ever, PKA is a general regulator of cell physiology and the con- sensitization of synaptic receptors. sequencesof PKA activation can include desensitization or po- tentiation of heterologousreceptor systems(Benovic et al., 1988; Synaptic signaltransduction, and the molecular events that con- Huganir and Greengard, 1990; Greengard et al., 1991; Wang et stitute this process,are fundamental to the function of neuronal al., 1991). In contrast, this laboratory has purified and char- circuits. Of particular interest are mechanismsby which the acterized PARK, a serine/threonine kinase activity that specif- strength of synaptic transmission may be either enhanced or ically phosphorylates the hormone-activated form of the &AR diminished. Regulation of neurotransmitter signal transduction (Benovic et al., 1987a). PARK-mediated receptor desensitiza- at the level of the synaptic receptor is a potentially important tion is, therefore, homologous in the sensethat only those re- mechanism of synaptic plasticity. A substantial body of evi- ceptorsbinding agonistare potential substrates.Moreover, PARK dence now suggeststhat phosphorylation events regulate the phosphorylation of the &AR itself causesonly minimal inhi- functions of both G-protein<oupled receptorsand ligand-gated bition of receptor-G, coupling (Benovic et al., 1987b). Instead, ion channel receptors (reviewed by Sibley et al., 1987; Klein et PARK phosphorylation promotes the associationof a cofactor, al., 1989; Huganir and Greengard, 1990). The functional con- p-arrestin, that is required to effect receptor desensitization(Lohse sequencesof G-protein<oupled receptor phosphorylation have et al., 1990). PARK phosphorylation of the &AR, therefore, been extensively studied using the &adrenergic receptor (&AR) representsa distinct pathway for homologousreceptor desen- sitization. Received Mar. 12, 1992; revised May 22, 1992; accepted May 27, 1992. PARK-mediated desensitizationmay be a generalmechanism We thank S. El Mestikawy, M. Hnatowich, R. Fremeau, J. Pitcher, H. Attra- that regulatesthe responsesof many G-protein-coupled recep- madal, C. Aoki, and C. Stone for advice and discussion. This work was supported by the Howard Hughes Medical Institute, by U.S. Public Health Service Grants tors. In addition to the &AR, purified PARK has been shown NS-26723 to R.B.S., AG-05146 and NS-20471 to L.J.M., DA-00266 and MH- to phosphorylate the a,,-adrenergic receptor (Benovic et al., 18501 to S.H.S., HL-16037 to R.J.L., and by Research Scientist Award DA-00074 1987c), the M, muscarinic ACh receptor (Kwatra et al., 1989) and a Sift from Bristol-Myers-Squibb to S.H.S. T.M.D is a Pfizer Postdoctoral Fellow and is supported by grants from the American Academy of Neurology, the and even the photoreceptor rhodopsin (Benovic et al., 1986) in French Foundation for Alzheimer’s Research, and the Dana Foundation. R.B.S. a stimulus-dependent manner. Although a full assessmentof is supported by a research award from the Theodore and Vada Stanley Foundation. the range of potential PARK substrateshas been limited by the Correspondence should be addressed to Robert J. Letkowitz, M.D., Box 3821, Duke University Medical Center, Durham, NC 277 10. availability of purified receptors, these data suggestthat stim- Copyright 0 1992 Society for Neuroscience 0270-6474/92/124045-l 1$05.00/O ulus-dependentphosphorylation by PARK is a common feature 4046 Arriza et al. - Synaptic Expression of @ARK1 and PARK2 of the G-protein-coupled receptor family. Furthermore, the re- 42 (Promega). This plasmid was linearized at the polylinker Hind111 quirement of receptor agonist-occupation for PARK phosphor- site for transcription with SP6 polymerase to produce antisense cRNA nrobe. nGEM-BARK2 contains a 42 1 bv DraVPstI fraament of &ARK2 ylation leads to the expectation that this desensitization pathway cDNA-inserted into the SmaI/PstI pofylinker sites 07 pGEM-4Z. This would be functionally important when receptors are exposed to plasmid was linearized at the polylinker EcoRI site for transcription high agonist concentrations, as occurs at the synapse (Hausdorff with T7 polymerase to generate antisense cRNA probe. et al., 1990). Accordingly, desensitization of neurotransmitter Fusion proteins expressed in Escherichia coli were generated using receptors via PARK might represent a general process regulating pGEX-2T (Pharmacia) constructs in which C-terminal coding sequences of rat PARK1 and PARK2 were ligated in-frame with sequences en- neurotransmission. coding glutathione-S-transferase (GST). Using the polymerase chain A significant step toward evaluating the role of PARK-me- reaction technique, sequences encoding amino acid sequences 467-689 diated desensitization in the nervous system would be to de- of rat BARK1 or residues 467-688 of rat PARK2 were synthesized with termine if the distribution of PARK expression is consistent flanking BamHI and EcoRI restriction sites for subcloning into BamHI- and EcoRI-cut pGEX-2T, forming plasmids pGEX-PlCT or pGEX- with its proposed general and synaptic functions. Recent de- /32CT. velopments from molecular cloning have provided the means Transfections, CO.97 cell extract preparation, and @JAR phosphory- to examine the expression of PARK as well as an additional lation. Functional assays for the rat pARK1 and PARK2 gene products complexity: two closely related, yet distinct, cDNA sequences were performed by transfecting COS-7 cells with expression plasmid, encoding “PARK” have been cloned from bovine brain (Be- harvesting cells for cytosolic extracts, and assaying these extracts for agonist-dependent phosphorylation of purified, lipid-reconstituted novic et al., 1989, 199 1). Since both gene products exhibit PARK- hamster &AR. Subconfluent COS-7 cells maintained in Dulbecco’s like characteristics (i.e., agonist-dependent phosphorylation of modified Eagle’s medium with 10% fetal calf serum were transfected by the P,AR), these kinases are referred to as PARK isozymes, with the DEAE-dextran method (Lopeta et al., 1984) with 30 r,rg of either the first gene isolated termed PARK1 and the second PARK2. pCMV-PARK1 or pCMV-PARK2 DNA per 150 mm plate. Control extracts were prepared from cells transfected with pCMV5. Cells were The pattern of expression for each PARK isozyme may reflect harvested 2 dafter transfection by scraping in 2 ml-of 50 mM Tris, pH its function. For example, each PARK isozyme could be asso- 7.5, 5 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride, 5 &ml ciated with a subset of G-protein-coupled receptors; if so, this pepstatin, and 10 &ml benzamidine, homogenized with a Brinkmann might be indicated by differences in the distributions of PARK1 tissue disruptor, and centrifuged at 3OCl,OOO x g for 20 min at 4°C. and @ARK2.
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