Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary cultures of rat preadipocytes were shown to express alpha 2- and beta-adrenoreceptors when maintained in serum-deprived medium. alpha 2-Adrenoreceptor stimulation led to an increase in cell number, whereas beta-adrenoreceptor stimulation was without effect. On 3T3-F442A clones stably transfected with the human alpha 2-C10 gene and expressing a physiologically related number of alpha 2-adrenoreceptors to overexpression, the proliferative effect of alpha 2-adrenoreceptor agonist UK14304 was proportional to the level of alpha 2-adrenoreceptor expressed in individual clones and required alpha-2 adrenoreceptor stimulation. Analysis of the signaling pathway linked to alpha 2-adrenoreceptor activation showed that the mitogenic effect was adenylyl cyclase- and protein kinase C-independent. It was pertussis toxin-sensitive, implying the involvement of pertussis toxin-sensitive G proteins. The activation of the mitogen-activated protein kinase pathway was increased after alpha 2-adrenoreceptor stimulation in both 3T3-F442 clones and rat preadipocytes and inhibited by pertussis toxin treatment. So, catecholamines are involved in the control of white preadipocyte proliferation through the alpha 2-adrenoreceptor activation, linked to the mitogen-activated protein kinase pathway.
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PMID:Alpha 2-adrenergic stimulation promotes preadipocyte proliferation. Involvement of mitogen-activated protein kinases. 798 35

A cAMP-dependent reporter gene has been used in transiently transfected human choriocarcinoma (JEG-3) cells to examine the second messenger coupling of the human alpha 2-adrenergic receptor subtypes. The reporter gene consists of a cAMP response element linked to the gene for chloramphenicol acetyltransferase (CAT). Plasmids encoding the alpha 2-C10 (alpha 2A), alpha 2-C2 (alpha 2B), or alpha 2-C4 (alpha 2C) receptor subtypes were co-transfected with a plasmid containing the reporter gene, and the ability of alpha 2 receptor agonists to influence forskolin-stimulated CAT expression was examined. For alpha 2-C10, agonists had a biphasic effect on forskolin-stimulated CAT expression. Thus, low (nanomolar) concentrations of agonist inhibited CAT expression by approximately 60%, whereas high (micromolar) concentrations reversed this inhibition and could even potentiate CAT expression by as much as 140%. A significantly different pattern of coupling was observed for the other alpha 2 receptor subtypes. For alpha 2-C4, agonists only inhibited forskolin-stimulated CAT expression, whereas for alpha 2-C2 only potentiation of expression was seen. Each of these responses was specifically blocked by alpha 2- but not alpha 1- or beta-adrenergic receptor antagonists. For alpha 2-C4, the inhibition of forskolin-stimulated CAT expression was prevented by pretreatment of the cells with pertussis toxin. This was also true for the inhibition obtained with alpha 2-C10. The potentiation of CAT expression, however, was not prevented by pertussis toxin pretreatment in cells transfected with either alpha 2-C2 or alpha 2-C10. In this transient expression system, each alpha 2-adrenergic receptor subtype had access to the same complement of G proteins, adenylyl cyclase, and other second messengers. It would appear, therefore, that the potential for the activation of unique intracellular responses exists even among closely related receptor subtypes.
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PMID:Selective coupling of alpha 2-adrenergic receptor subtypes to cyclic AMP-dependent reporter gene expression in transiently transfected JEG-3 cells. 823 31

Cholera toxin-catalysed [32P]ADP-ribosylations were performed in the absence of guanine nucleotides on membranes of a clone (1C) of Rat 1 fibroblasts which express high levels of the alpha 2-C10 adrenergic receptor. As well as incorporation of radioactivity into 45,000 and 42,000 M(r) polypeptides which represent forms of Gs alpha, there was weak labelling of a 40,000 M(r) polypeptide(s). Addition of the alpha 2 adrenergic agonist UK14304 to such assays enhanced markedly the incorporation of radioactivity into the 40,000 M(r) polypeptide(s) but did not alter labelling of the forms of Gs. We have previously demonstrated that the 40,000 M(r) polypeptide(s) labelled in such a manner represents a combination of the alpha subunits of Gi2 and Gi3 [Milligan et al. (1991) J. biol. Chem. 266, 6447-6455]. Mercuric acetate treatment of membranes prelabelled with [32P]ADP-ribose by exposure to pertussis toxin and [32P]NAD removed totally the radiolabel from both Gi2 and Gi3. However, cholera toxin-catalysed [32P]ADP-ribosylation of either the alpha subunits of the Gi-subtypes or of forms of Gs was unaffected by such treatment. By contrast, prolonged, but not short-term, exposure to neutral hydroxylamine removed radiolabel incorporated by cholera toxin from the Gi-subtypes and from Gs but did not remove [32P]ADP-ribose incorporated by pertussis toxin from the Gi-subtypes. It is concluded that ADP-ribosylation of pertussis toxin-sensitive G-proteins by cholera toxin, which can be induced by exposure of membranes to agonists for receptors which interact with that G-protein, is at an arginine residue. It is suggested that this residue may be Arg 179 in Gi2 alpha and Arg 178 in Gi3 alpha.
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PMID:An arginine residue is the site of receptor-stimulated, cholera toxin-catalysed ADP-ribosylation of pertussis toxin-sensitive G-proteins. 839 64

alpha 2-adrenergic receptors mediate many of the physiological actions of the endogenous catecholamines adrenaline and noradrenaline, and are targets of several therapeutic agents. alpha 2-adrenoceptor agonists are currently used as antihypertensives and as veterinary sedative anaesthetics. They are also used in humans as adjuncts to anaesthesia, as spinal analgesics, and to treat opioid, nicotine and alcohol dependence and withdrawal. Three human alpha 2-adrenoceptor subtype genes have been cloned and designated alpha 2-C10, alpha 2-C4, and alpha 2-C2, according to their location on human chromosomes 10, 4 and 2. They correspond to the previously identified pharmacological receptor subtypes alpha 2A, alpha 2C and alpha 2B. The receptor proteins share only about 50% identity in their amino acid sequence, but some structurally and functionally important domains are very well conserved. The most obvious functionally important differences between the receptor subtypes are based on their different tissue distributions; e.g. the alpha 2A subtype appears to be an important modulator of noradrenergic neurotransmission in the brain. The three receptors bind most alpha 2-adrenergic drugs with similar affinities, but some compounds (e.g. oxymetazoline) are capable of discriminating between the subtypes. Clinically useful subtype selectivity cannot be achieved with currently available pharmaceutical agents. The second messenger pathways of the three receptors show many similarities, but small functional differences between the subtypes may turn out to have important pharmacological and clinical consequences. All alpha 2-adrenoceptors couple to the pertussis-toxin sensitive inhibitory G proteins Gi and G(o), but recent evidence indicates that also other G proteins may interact with alpha 2-adrenoceptors, including Gs and Gq/11. Inhibition of adenylyl cyclase activity, which results in decreased formation of cAMP, is an important consequence of alpha 2-adrenoceptor activation. Many of the physiological effects of alpha 2-adrenoceptor activation cannot, however, be explained by decreases in cAMP formation. Therefore, alternative mechanisms have been sought to account for the various effects of alpha 2-adrenoceptor activation on electrophysiologic, secretory and contractile cellular responses. Recent results obtained from studies on ion channel regulation point to the importance of calcium and potassium channels in the molecular pharmacology of alpha 2-adrenoceptors.
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PMID:Molecular pharmacology of alpha 2-adrenoceptor subtypes. 851 5

The baculovirus expression vector system utilizing the strong polyhedrin gene promoter of the Autographa californica nuclear polyhedrosis virus (AcNPV) was used for high level expression of the two alpha 2-adrenoceptor subtypes alpha 2A-C10 and alpha 2B-C2 in Spodoptera frugiperda (Sf-9) insect cells. For rapid screening of recombinant viruses the luciferase gene was expressed under the early ETL-promoter (early transcript large) in the same plasmid. Both receptor subtypes showed the same rank order of binding affinity for four agonists tested: dexmedetomidine > l-medetomidine = clonidine > noradrenaline. For the alpha 2A-C10 subtype, these agonists inhibited forskolin stimulated cAMP production through pertussis toxin sensitive G-proteins. In contrast, for the alpha 2B-C2 subtype the agonists stimulated both basal and forskolin stimulated cAMP production.
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PMID:Two human alpha 2-adrenoceptor subtypes alpha 2A-C10 and alpha 2B-C2 expressed in Sf9 cells couple to transduction pathway resulting in opposite effects on cAMP production. 857 36

The molecular mechanisms of action of natural and synthetic polycationic peptides, forming amphiphilic helices, on the heterotrimeric G-proteins and enzyme adenylyl cyclase (AC), components of hormone-sensitive AC system, were studied. It is shown that synthetic peptides C-epsilonAhx-WKK(C10)-KKK(C10)-KKKK(C10)-YKK(C10)-KK (peptide I) and (GRGDSGRKKRRQRRRPPQ)2-K-epsilonAhx-C(Acm)(peptide II) in dose-dependent manner stimulate the basal AC activity, inhibit forskolin-stimulated AC activity and decrease both stimulating and inhibiting AC effects of the hormones in the tissues (brain striatum, heart muscle) of rat and in smooth muscles of the mollusc Anodonta cygnea. AC effects of these peptides are decreased after membrane treatment by cholera and pertussis toxins and are inhibited in the presence of the peptides, corresponding to C-terminal regions 385-394 alphas- and 346-355 alphai2-subunits of G-proteins. These data give evidence that the peptides I and II act on the signaling pathways which are realized through Gs- and Gi-proteins. At the same time, natural polycationic peptide mastoparan acts on AC system through Gi-proteins and blocks hormonal signals mediated via Gi-proteins only. Consequently, the action of mastoparan on G-proteins is selective and differs from the action of the synthetic peptides. It is also shown that peptide II, with branched structure, directly interacts not only with G-proteins (less effective in comparison with peptide I with hydrophobic radicals and mastoparan), but also with enzyme AC, the catalytic component of AC system. On the basis of data obtained the following conclusions were made: 1) the formation of amphiphilic helices is not enough for selective activation of G-protein by polycationic peptides, and 2) the primary structure of the peptides, the distribution of positive charged amino acids and hydrophobic radicals in them are very important for selective interaction between polycationic peptides and G-proteins.
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PMID:[Comparative study of molecular mechanisms of natural and synthetic polycationic peptides action on the activity of the adenylyl cyclase signaling system]. 1689 55

Lipopolysaccharides are anchored to the outer membrane of Gram-negative bacteria by a hydrophobic moiety known as lipid A, which potently activates the host innate immune response. Lipid A of Bordetella pertussis, the causative agent of whooping cough, displays unusual structural asymmetry with respect to the length of the acyl chains at the 3 and 3' positions, which are 3OH-C10 and 3OH-C14 chains, respectively. Both chains are attached by the acyltransferase LpxA, the first enzyme in the lipid A biosynthesis pathway, which, in B. pertussis, has limited chain length specificity. However, this only partially explains the strict asymmetry of lipid A. In attempts to modulate the endotoxicity of B. pertussis lipid A, here we expressed the gene encoding LpxA from Neisseria meningitidis, which specifically attaches 3OH-C12 chains, in B. pertussis This expression was lethal, suggesting that one of the downstream enzymes in the lipid A biosynthesis pathway in B. pertussis cannot handle precursors with a 3OH-C12 chain. We considered that the UDP-diacylglucosamine pyrophosphohydrolase LpxH could be responsible for this defect as well as for the asymmetry of B. pertussis lipid A. Expression of meningococcal LpxH in B. pertussis indeed resulted in new symmetric lipid A species with 3OH-C10 or 3OH-C14 chains at both the 3 and 3' positions, as revealed by MS analysis. Furthermore, co-expression of meningococcal lpxH and lpxA resulted in viable cells that incorporated 3OH-C12 chains in B. pertussis lipid A. We conclude that the asymmetry of B. pertussis lipid A is determined by the acyl chain length specificity of LpxH.
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PMID:Substrate specificity of the pyrophosphohydrolase LpxH determines the asymmetry of Bordetella pertussis lipid A. 3092 8


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