Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Olfaction is mediated by G protein-coupled receptors. In isolated rat olfactory cilia, odorants such as citralva stimulate a burst of cAMP, which peaks in 50 ms and returns almost to base-line level within 150 ms in the continuing presence of odorant. This desensitization is mediated by the cAMP dependent protein kinase and a specialized G protein-coupled receptor kinase originally termed beta ARK2 (GRK3). In vitro experiments suggest that the prenylated beta gamma-subunits of heterotrimeric G proteins target the cytosolic beta ARK1 (GRK2) enzyme to its membrane bound receptor substrate by binding to sites in its carboxyl terminus. Here we demonstrate that odorants stimulate translocation of GRK3 from cytosol to membranes in isolated rat olfactory cilia. We introduced a glutathione S-transferase-GRK3ct fusion protein, containing the carboxyl-terminal 222 amino acid residues of GRK3, which includes the beta gamma binding site, or a 28-amino acid peptide derived therefrom, into permeabilized cilia preparations. These reagents block odorant-mediated enzyme translocation and desensitization while markedly attenuating odorant-stimulated phosphorylation of olfactory proteins. These findings suggest that beta gamma-subunits may physiologically regulate a G protein-coupled receptor kinase and that enzyme translocation may be a general and required feature of the activity of some members of this enzyme family.
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PMID:Olfactory desensitization requires membrane targeting of receptor kinase mediated by beta gamma-subunits of heterotrimeric G proteins. 827 21

We have characterized a murine protein kinase gene, rck, which was identified by crosshybridization with sequences from the v-ros tyrosine kinase gene under conditions of reduced stringency. cDNA analysis indicated that rck encodes a putative protein kinase related to the cdc2 subclass of the gene family and that the gene is identical to mak identified previously in the rat. An extensive expression analysis in the mouse performed by a combination of in situ hybridization and RNase protection revealed a novel and restricted pattern of expression: rck transcripts are found in two cell types involved in sensory transduction, photoreceptors and olfactory receptors as well as in epithelia of the respiratory tract and choroid plexus. Specific transcripts are also found in pre- and postmeiotic male germ cells. We suggest therefore that rck participates in signalling pathways important in a distinct set of cells, remarkably among them cells involved in sensory signal transduction.
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PMID:Characterization and expression analysis of the murine rck gene: a protein kinase with a potential function in sensory cells. 835 91

We have previously shown that second-messenger-dependent kinases (cAMP-dependent kinase, protein kinase C) in the olfactory system are essential in terminating second-messenger signaling in response to odorants. We now document that subtype 2 of the beta-adrenergic receptor kinase (beta ARK) is also involved in this process. By using subtype-specific antibodies to beta ARK-1 and beta ARK-2, we show that beta ARK-2 is preferentially expressed in the olfactory epithelium in contrast to findings in most other tissues. Heparin, an inhibitor of beta ARK, as well as anti-beta ARK-2 antibodies, (i) completely prevents the rapid decline of second-messenger signals (desensitization) that follows odorant stimulation and (ii) strongly inhibits odorant-induced phosphorylation of olfactory ciliary proteins. In contrast, beta ARK-1 antibodies are without effect. Inhibitors of protein kinase A and protein kinase C also block odorant-induced desensitization and phosphorylation. These data suggest that a sequential interplay of second-messenger-dependent and receptor-specific kinases is functionally involved in olfactory desensitization.
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PMID:A beta-adrenergic receptor kinase-like enzyme is involved in olfactory signal termination. 838 66

1. Single calcium-activated potassium channels (KCa channels) were recorded from membrane patches of rat olfactory bulb neurons in culture. Only one kind of KCa channel was seen, and it was present in approximately 50% of detached patches. 2. This channel, like maxi-KCa channels of other tissues, had a single-channel conductance of 270 pS, a reversal potential (Erev) of 0 mV in symmetrical K+, and was highly selective for K+ over Na+ and Cl-. 3. The KCa channel was blocked by d-tubocurarine (d-TC) on the cytoplasmic side, and charybdotoxin (CTX) on the extracellular side. This pharmacology is identical to that of one type of KCa channel from rat brain, observed previously in artificial bilayers and called the type 1 KCa channel. 4. The probability that the channel was in the open state (Po) increased with membrane depolarization. The position of the Po versus transmembrane voltage (Vm) curve was shifted by changes in [Ca2+]i so that the channel was open more often in higher [Ca2+]i. The gating kinetics resembled those of the type 1 KCa channel observed in bilayers. 5. Po was increased after superfusion of the cytoplasmic membrane surface with the active catalytic subunit of cyclic AMP-dependent protein kinase (PK-A), together with MgATP. Phosphorylation altered the distribution of channel closed times but had little effect on open times. The results suggest that phosphorylation is an important molecular mechanism in modulating the activity of this KCa channel from mammalian brain.
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PMID:Properties and modulation of a calcium-activated potassium channel in rat olfactory bulb neurons. 838 24

We have isolated and characterized a rat brain cDNA clone which encodes a new protein of 474 amino acids in length which contains two C2 domains structurally homologous to those present in synaptotagmins. The overall amino acid identity in C2 domains between this protein and the synaptotagmins is 36-44%. This protein also contains 3 putative consensus sequences for phosphorylation by cAMP-dependent protein kinase. RNA blot hybridization revealed a 3.0 kb transcript abundantly expressed only in the rat brain and the kidney. Thus, we called this brain/kidney protein (B/K). In situ hybridization and Northern blot analyses showed that the B/K transcript was found in forebrain including the olfactory bulb, cerebral cortex, hippocampus, and hypothalamus. In the kidney, high levels of B/K transcript were expressed in the papillary region of the inner medulla, the inner stripe of the outer medulla and the cortex. The selective expression in forebrain and kidney suggests that B/K may be involved in similar cAMP-dependent processes at these very different sites.
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PMID:Identification of a novel protein containing two C2 domains selectively expressed in the rat brain and kidney. 854 19

The cyclic AMP (cAMP) system plays a critical role in olfactory learning in the fruit fly, Drosophila melanogaster, as evidenced by the following: [1] The dunce gene encodes a form of cAMP phosphodiesterase (PDE). Flies carrying mutations at this gene show reduced PDE activity, high cAMP levels, and deficits in olfactory learning and memory [2]. The rutabaga gene encodes one type of adenylyl cyclase (AC) similar in properties to the Type I AC characterized from vertebrate brain. This enzyme is activated by G-protein and Ca++ and has been postulated to be a molecular coincidence detector, capable of integrating information from two independent sources such as the conditioned stimulus (CS) and the unconditioned stimulus (US) delivered to animals during Pavlovian conditioning. Rutabaga mutant flies are deficient in AC activity and show behavioral defects similar to those exhibited by dunce mutants [3]. Flies carrying mutations in the gene (DC0) that encodes the catalytic subunit of protein kinase A (PKA), the major mediator of cAMP actions, show alterations in learning performance and a loss in PKA activity. All three genes are expressed preferentially in mushroom bodies, neuroanatomical sites that mediate olfactory learning. Interestingly, the PDE and the catalytic subunit of PKA are found primarily in axonal and dendritic compartments of the mushroom body cells, whereas the AC is found primarily in the axonal compartment. The reason for this differential compartmentalization is unclear, although the hypothetical role of AC as coincidence detector would predict that CS and US stimuli are integrated in the axonal compartment. These observations suggest that cAMP is a dominant second messenger utilized by mushroom body cells to modulate their physiology while the animal is learning and consolidating memory. However, many other types of molecules are likely involved in the physiological alterations that occur in these cells during learning, including cell surface proteins, transcription factors, and synaptic proteins.
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PMID:The cyclic AMP system and Drosophila learning. 856 40

Strong odor stimuli elicit a slow and sustained increase of the cGMP concentration in isolated rat olfactory cilia. Elevated cGMP levels appear to attenuate the primary response to odorant stimulation. Incubating cilia with membrane-permeable cGMP derivates caused a significantly reduced cAMP signal in response to odorant stimulation. This inhibitory effect was mimicked by 8-(4-chlorophenlythio)-cGMP, a selective activator of cGMP-activated protein kinases; in contrast, a selective inhibitor, [8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate] of cGMP kinases enhanced the reactivity to odorant stimulation. The data suggest that the responsiveness of olfactory sensory cells is governed by a cGMP-dependent protein kinase. Western-blot analysis using subtype-specific antibodies indicated that cytosolic type-I cGMP kinase, but not the membrane-associated type-II cGMP kinase, is expressed in olfactory sensory neurons.
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PMID:Regulation of olfactory signalling via cGMP-dependent protein kinase. 861 39

Inhibition of type III adenylyl cyclase (III-AC) by intracellular Ca2+ in vivo provides a mechanism for attenuation of hormone-stimulated cAMP signals in olfactory epithelium, heart, and other tissues (Wayman, G. A., Impey, S., and Storm, D. R. (1995) J. Biol. Chem. 270, 21480-21486). Although the mechanism for Ca2+ inhibition of III-AC in vivo has not been defined, inhibition is not mediated by Gi, cAMP-dependent protein kinase, or protein kinase C. However, Ca2+ inhibition of III-AC is antagonized by KN-62, a CaM-dependent kinase inhibitor. In addition, constitutively activated CaM kinase II inhibits the enzyme. These data suggest that CaM kinase II regulates the activity of III-AC by direct phosphorylation or by an indirect mechanism involving phosphorylation of a protein that inhibits III-AC. Here we report that III-AC is phosphorylated in vivo when intracellular Ca2+ is increased and that phosphorylation is prevented by CaM-dependent kinase inhibitors. Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo. These data support the hypothesis that Ca2+ inhibition of III-AC is due to direct phosphorylation of the enzyme by CaM kinase II in vivo.
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PMID:Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. 879 67

Phosducin, which tightly binds betagamma-subunits of heterotrimeric G-proteins, has been conjectured to play a role in regulating second messenger signaling cascades, but to date its specific function has not been elucidated. Here we demonstrate a potential role for phosducin in regulating olfactory signal transduction. In isolated olfactory cilia certain odorants elicit a rapid and transient cAMP response, terminated by a concerted process which requires the action of two protein kinases, protein kinase A (PKA) and a receptor-specific kinase (GRK3) (Schleicher, S., Boekhoff, I. Arriza, J., Lefkowitz, R. J., and Breer, H. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 1420-1424). The mechanism of action of GRK3 involves a Gbetagamma-mediated translocation of the kinase to the plasma membrane bound receptors (Pitcher, J. A., Inglese, J., Higgins, J. B. , Arriza, J. L., Casey, P. J., Kim, C., Benovic, J. L., Kwatra, M. M. , Caron, M. G., and Lefkowitz, R. J. (1992) Science 257, 1264-1267). A protein with a molecular mass of 33 kDa that comigrates on SDS gels with recombinant phosducin and which is immunoreactive with phosducin antibodies is present in olfactory cilia. Recombinant phosducin added to permeabilized olfactory cilia preparations strongly inhibits termination of odorant-induced cAMP response and odorant-induced membrane translocation of GRK3. In addition, the cAMP analogue dibutyryl cAMP stimulates membrane targeting of the receptor kinase. This effect is presumably due to PKA-mediated phosphorylation of phosducin, which diminishes its affinity for binding to the Gbetagamma-subunit, thereby making Gbetagamma available to function as a membrane anchor for GRK3. A specific PKA inhibitor blocks the odorant-induced translocation of the receptor kinase. Consistent with this formulation, a non-phosphorylatable mutant of phosducin (phosducin Ser-73 --> Ala) is an even more effective inhibitor of desensitization and membrane targeting of GRK3 than the wild-type protein. A phosducin mutant that mimics phosphorylated phosducin (phosducin Ser-73 --> Asp) lacks this property and in fact recruits GRK3 to the membrane and potentiates desensitization. These results suggest that phosducin may act as a phosphorylation-dependent switch in second messenger signaling cascades, regulating the kinetics of desensitization processes by controlling the activity of Gbetagamma-dependent GRKs.
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PMID:Phosducin, potential role in modulation of olfactory signaling. 902 Jan 89

Compartmentalization of cAMP-dependent protein kinase is achieved in part by interaction with A-kinase anchoring proteins (AKAPs). All of the anchoring proteins identified previously target the kinase by tethering the type II regulatory subunit. Here we report the cloning and characterization of a novel anchoring protein, D-AKAP1, that interacts with the N terminus of both type I and type II regulatory subunits. A novel cDNA encoding a 125-amino acid fragment of D-AKAP1 was isolated from a two-hybrid screen and shown to interact specifically with the type I regulatory subunit. Although a single message of 3.8 kilobase pairs was detected for D-AKAP1 in all embryonic stages and in most adult tissues, cDNA cloning revealed the possibility of at least four splice variants. All four isoforms contain a core of 526 amino acids, which includes the R binding fragment, and may be expressed in a tissue-specific manner. This core sequence was homologous to S-AKAP84, including a mitochondrial signal sequence near the amino terminus (Lin, R. Y., Moss, S. B., and Rubin, C. S. (1995) J. Biol. Chem. 270, 27804-27811). D-AKAP1 and the type I regulatory subunit appeared to have overlapping expression patterns in muscle and olfactory epithelium by in situ hybridization. These results raise a novel possibility that the type I regulatory subunit may be anchored via anchoring proteins.
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PMID:Identification of a novel protein kinase A anchoring protein that binds both type I and type II regulatory subunits. 906 79


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