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

The chimeric peptide M35 [galanin(1-13)-bradykinin(2-9) amide] is a high-affinity galanin receptor ligand acting as a galanin receptor antagonist in the rat spinal cord, rat hippocampus and isolated mouse pancreatic islets. We have radiolabelled M35 and performed equilibrium binding studies with [125I]M35 on the rat pancreatic beta-cell line Rin m 5F, whereby we show the existence of high-affinity binding site (KD = 0.9 +/- 0.1 nM) with a Bmax of 72 +/- 3 fmol/mg protein. Galanin displaces [125I]M35 with the same affinity (KD = 1 nM) as it displaces [125I]galanin. Displacement of [125I]galanin by M35 from Rin m 5F cell membranes shows the presence of two binding sites for M35 with KD-values of 0.3 +/- 0.1 nM and 0.52 +/- 0.03 microM, respectively. The GTP- and pertussis toxin-sensitivity of M35 binding to Rin m 5F membranes shows that binding of [125I]M35 is almost completely abolished by the presence of GTP or after pertussis toxin treatment of the cells, indicating an agonist-like binding of M35 to the galanin receptors. M35 has a dual effect on the galanin mediated inhibition of forskolin stimulated cyclic AMP production in Rin m 5F cells: at low concentrations M35 antagonises the effect of galanin, whereas at concentrations above 10 nM M35 acts as a galanin receptor agonist. These agonist-like effects of galanin and M35 are not additive, thus the mixed agonist/antagonist properties arise from the chimeric nature of M35[galanin(1-13)-bradykinin(2-9)amide] acting solely at galanin receptors.
 ...
PMID:Binding and agonist/antagonist actions of M35, galanin(1-13)-bradykinin(2-9)amide chimeric peptide, in Rin m 5F insulinoma cells. 857 39

Galanin is a ubiquitous neuropeptide that regulates a wide array of physiological processes via interaction with specific G protein-coupled receptors. A rat galanin receptor cDNA was cloned from the Rin14B insulinoma cell line. The isolated cDNA encodes a 346 amino acid G protein-coupled receptor that is 92% identical to the recently reported human GALR1 galanin receptor. [125I]Galanin binds with high affinity to two receptor states in COS1 cell membranes containing the rat GALR1 receptor, consistent with coupling of the receptor to a G protein in these membranes. N-terminal galanin fragments and the putative galanin receptor antagonists galantide, C7, M35 and M40 bind with high affinity to the rat GALR1 receptor. In contrast, C-terminal galanin fragments do not bind to this receptor. Galanin inhibits basal and forskolin-stimulated cAMP formation in CHO cells expressing the rat GALR1 receptor via a pertussis toxin-sensitive G protein. The GALR1 receptor is expressed in rat spinal cord, small intestine, Rin14B insulinoma cells and several brain regions, particularly ventral hippocampus, amygdala, supraoptic nucleus, hypothalamus, thalamus, lateral parabrachial nucleus and locus coeruleus. Cloning of the rat GALR1 galanin receptor cDNA will permit many new experimental strategies to be applied to studies of the structure and function of galanin receptors.
 ...
PMID:Cloning and characterization of the rat GALR1 galanin receptor from Rin14B insulinoma cells. 875 Aug 21

Activated receptors for galanin and norepinephrine, and for several other agonists, inhibit insulin release from pancreatic beta-cells via pertussis toxin-sensitive Gi- and Go-proteins and by acting on at least four cellular mechanisms. These mechanisms include repolarization via activation of the ATP-sensitive potassium (K ATP) channel, inhibition of adenylyl cyclase, and inhibition by unknown mechanism at a "distal" site. For norepinephrine and galanin there is also inhibition of the L-type Ca2+ channel. Consequently, during simultaneous activation by multiple agonists, the effectiveness with which a receptor interacts with the G-proteins will, to some extent, determine the responses. This could have important consequences for the beta-cell. Therefore, the G-protein interactions of two activated receptors, those for norepinephrine and galanin, were compared in the same beta-cell membranes. Measurements were made of the rates of receptor-G-protein interaction (by GTPgammaS binding) and of the rates of turnover of G-proteins (by GTPase activity). A comparison was also made of the ability of norepinephrine and galanin to facilitate ADP ribosylation of the alpha-subunits of Gi and Go by cholera toxin (CTX). Such CTX-induced ADP ribosylation of Gi and Go occurs during G-protein interaction with an activated receptor. By measurement of the number of receptors in the membrane preparation used, the relative effectiveness of the two receptors was assessed. The alpha2-adrenergic receptor was found to be markedly more effective than the galanin receptor in activating G-proteins.
 ...
PMID:The alpha2-adrenergic receptor is more effective than the galanin receptor in activating G-proteins in RINm5F beta-cell membranes. 903 95

The neuropeptide galanin mediates a diverse spectrum of biological activities by interacting with specific G-protein-coupled receptors. Through expression cloning, human and rat GALR1 receptor cDNA clones have previously been isolated and characterized. In this study, we have used homology screening to isolate a rat brain cDNA clone encoding a second galanin receptor subtype, the GALR2 receptor. The isolated cDNA encodes a 372-amino-acid G-protein-coupled receptor that shares 38% overall amino-acid identity with the rat GALR1 receptor. The pharmacological profile of the rat GALR2 receptor is similar to that of the rat GALR1 receptor. The rat GALR2 receptor binds galanin, N-terminal galanin fragments, and the putative galanin receptor antagonists galantide, C7, M35 and M40 with high affinity but it does not bind C-terminal galanin fragments. Galanin increases intracellular inositol phosphate levels in HEK 293 cells expressing the rat GALR2 receptor via a pertussis toxin-insensitive G-protein. The rat GALR2 receptor mRNA is highly expressed in several brain regions, including hypothalamus and hippocampus as well as the anterior pituitary, with lower levels of expression detected in amygdala, and regions of cortex. It is also highly expressed in the GH3 pituitary cell line and in gut tissues, and to a lower extent in spleen, lung, skeletal muscle, heart, kidney, liver and testis. These results suggest that GALR2 receptor mediates galanin's regulation of pituitary hormone secretion and possibly food intake.
 ...
PMID:Cloning, pharmacological characterization and distribution of a novel galanin receptor. 942 6

The diverse physiological functions exerted by the neuropeptide galanin may be regulated by multiple G protein-coupled receptor subtypes and intracellular signaling pathways. Three galanin receptor subtypes (GalRs) have been recently cloned, but the G protein coupling profiles of these receptors are not completely understood. We have generated GalR1- and GalR2-expressing Chinese hamster ovary (CHO) cell lines and systematically examined the potential for these two receptors to couple to the Gs, Gi, Go, and Gq proteins. Galanin did not stimulate an increase in cAMP levels in GalR1/CHO or GalR2/CHO cells, suggesting an inability of either receptor to couple to Gs. Galanin inhibited forskolin-stimulated cAMP production in GalR1/CHO cells by 70% and in GalR2/CHO cells by 30%, suggesting a strong coupling of GalR1 to Gi and a more modest coupling between GalR2 and Gi. GalR1 and GalR2 both mediated pertussis toxin-sensitive MAPK activity (2-3-fold). The stimulation mediated by GalR1 was inhibited by expression of the C-terminus of beta-adrenergic receptor kinase (beta ARKct), which specifically inhibits G beta gamma signaling, but was not affected by the protein kinase C (PKC) inhibitor, bis[indolylmaleimide], or cellular depletion of PKC. In contrast, GalR2-mediated MAPK activation was not affected by beta ARKct expression but was abolished by inhibition of PKC activity. The data demonstrate that GalR1 is coupled to a Gibetagamma signaling pathway to mediate MAPK activation. In contrast, GalR2 utilizes a distinct signaling pathway to mediate MAPK activation, which is consistent with Go-mediated MAPK activation in CHO cells. Galanin was unable to stimulate inositol phosphate (IP) accumulation in CHO or COS-7 cells expressing GalR1. In contrast, galanin stimulated a 7-fold increase in IP production in CHO or COS-7 cells expressing GalR2. The GalR2-mediated IP production was not affected by pertussis toxin, suggesting a linkage of GalR2 with Gq/G11. Thus, the GalR1 receptor appears to activate only the Gi pathway. By contrast, GalR2 is capable of stimulating signaling which is consistent with activation of Go, Gq/G11, and Gi. The differential signaling profiles and the tissue distribution patterns of GalR1 and GalR2 may underlie the functional spectra of galanin action mediated by these galanin receptors and regulate the diverse physiological functions of galanin.
 ...
PMID:Differential intracellular signaling of the GalR1 and GalR2 galanin receptor subtypes. 957 54

The diverse physiological actions of galanin are thought to be mediated through activation of galanin receptors (GalRs). We report the genomic and cDNA cloning of a mouse GalR that possesses a genomic structure distinct from that of GalR1 and encodes a functional galanin receptor. The mouse GalR gene consists of two exons separated by a single intron within the protein-coding region. The splicing site for the intron is located at the junction between the third transmembrane domain and the second intracellular loop. The cDNA encodes a 370-amino acid putative G protein-coupled receptor that is markedly different from human GalR1 and rat GalR3 (38 and 57%) but shares high homology with rat GalR2 (94%). In binding studies utilizing membranes from COS-7 cells transfected with mouse GalR2 cDNA, the receptor displayed high affinity (K(D) = 0.47 nM) and saturable binding with 125I-galanin (Bmax = 670 fmol/mg). The radioligand binding can be displaced by galanin and its analogues in a rank order: galanin approximately = M40 approximately = M15 approximately = M35 approximately = C7 approximately = galanin(2-29) approximately = galanin(1-16) >> galanin(10-29) approximately = galanin(3-29), which resembles the pharmacological profile of the rat GalR2. Receptor activation by galanin in COS-7 cells stimulated phosphoinositide metabolism, which was not reversed by pertussis toxin. Thus, the galanin receptor encoded in the cloned mouse GalR gene is the type 2 galanin receptor and is active in both ligand binding and signaling assays.
 ...
PMID:The mouse GalR2 galanin receptor: genomic organization, cDNA cloning, and functional characterization. 983 22

Galanin-induced activation of an inwardly rectifying membrane potassium (K+) current and inhibition of barium current (IBa) were studied using whole cell voltage clamp recording techniques in parasympathetic neurons dissociated from the mudpuppy cardiac ganglion. Both activation of the K+ current and inhibition of IBa were concentration-dependent with an EC50 (or IC50) of approximately 35 nM and approximately 0.4 nM, respectively. Both actions of galanin were eliminated by pretreatment with pertussis toxin, which suggested involvement of Gi/Go protein activation. Galantide antagonized the galanin-induced activation of K+ current with an IC50 equal to 4 nM. By contrast, galantide, by itself, inhibited IBa with an EC50 equal to 16 nM. Another galanin analog, M40, primarily antagonized the galanin-induced activation of K+ current, but in some cells, M40 also acted as a weak agonist. M40, like galantide, inhibited IBa. The NH2-terminal fragment galanin-(1-16) activated the K+ current and inhibited IBa, indicating that the first 16 amino acids of the galanin peptide were sufficient for both actions. In summary, it is postulated that the effects of galanin on mudpuppy parasympathetic neurons might be mediated by activation of two different subtypes of galanin receptor, one that regulates membrane K+ conductance and a second that modulates calcium conductance.
 ...
PMID:Galanin activates an inwardly rectifying potassium conductance and inhibits a voltage-dependent calcium conductance in mudpuppy parasympathetic neurons. 992 68

Galanin has been implicated in various physiological functions including memory, feeding and pain perception. Using rat cerebral cortical slices and synaptosome preparations incubated with [(3)H]choline in Kreb's-Ringer solution, galanin was shown to inhibit both spontaneous and K(+)-stimulated [(3)H]ACh release in a concentration-related manner [EC(50)= 35 nM]. The galanin-mediated inhibition on spontaneous and K(+)-stimulated [(3)H]ACh release was respectively regulated by pertussis toxin-sensitive G(alphai3)and G(alphai1). These suggest that galanin is a negative modulator of cortical cholinergic function and most probably acting on presynaptic cholinergic terminals. Although galantide blocked the galanin-mediated inhibitory effect on [(3)H]ACh release, it mimicked galanin in blocking K(+)-stimulated [(3)H]ACh release, indicating that galantide may have a more complicated pharmacology than being a galanin receptor antagonist. In addition, we demonstrate that galanin and beta-amyloid peptide(1-42)synergistically attenuated K(+)-evoked [(3)H]ACh release from synaptosomes prepared from rat cerebral cortex. Since galanin is increased in Alzheimer's disease brain, our results suggest that galanin may be involved in cholinergic dysfunctions that occur in Alzheimer's disease.
 ...
PMID:Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive G(i)protein. 1065 92

Neuropeptides like galanin produced and released by small cell lung cancer (SCLC) cells are considered principal mitogens in these tumors. We identified the galanin receptor type 2 (GALR2) as the only galanin receptor expressed in H69 and H510 cells. Photoaffinity labeling of G proteins in H69 cell membranes revealed that GALR2 activates G proteins of three subfamilies: G(q), G(i), and G(12). In H69 cells, galanin-induced Ca2+ mobilization was pertussis toxin-insensitive. While phorbol ester-induced extracellular signal-regulated kinase (ERK) activation required protein kinase C (PKC) activity, preincubation of H69 cells with the PKC-inhibitor GF109203X had no effect on galanin-dependent ERK activity. A rise of the intracellular calcium concentration was necessary and sufficient to mediate galanin-induced ERK activation. In support of G(i) coupling, stimulation of GALR2 expressed in HEK293 cells inhibited isoproterenol-induced cAMP accumulation and raised cAMP levels in COS-7 cells when coexpressed with a chimeric G alpha(S)-G alpha(i) protein In H69 cells, galanin activated the monomeric GTPase RhoA and induced stress fiber formation in Swiss 3T3 cells expressing GALR2. Thus, we provide the first direct evidence that in SCLC the mitogenic neuropeptide galanin, interacting with GALR2, simultaneously activates multiple classes of G proteins and signals through the G(q) phospholipase C/calcium sequence and a G(12)/Rho pathway. Oncogene (2000) 19, 4199 - 4209
 ...
PMID:The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to G(q), G(i) and G(12) proteins. 1098 May 93

Whole-cell patch-clamp recording methods were used to investigate the ionic mechanisms underlying the hyperpolarizing action of galanin in enteric neurones. Galanin suppressed calcium current (ICa) and activated inwardly rectifying potassium current (IK,ir) in AH-type myenteric neurones of guinea-pig small intestine. Both suppression of ICa and activation of IK,ir were concentration-dependent, with an EC50 of 1.4 nmol L-1 and 55 nmol L-1, respectively. Pretreatment with pertussis toxin eliminated both actions of galanin, suggesting that both galanin-induced inhibition of ICa and galanin-induced activation of IK,ir involved activation of Gi/Go proteins. Both suppression of ICa and activation of IK,ir by galanin were mimicked by the N-terminal fragment of galanin, galanin-(1-16) suggesting that the first 16 amino acids of the peptide were sufficient for both actions. The galanin receptor antagonist galantide suppressed the galanin-induced activation of IK,ir with an EC50 of 16 nmol L-1. However, galantide alone suppressed ICa. The results suggest two mechanisms of action for galanin: one is opening of inwardly rectifying potassium channels and the second is blockade of voltage-activated calcium channels.
 ...
PMID:Galanin suppresses calcium conductance and activates inwardly rectifying potassium channels in myenteric neurones from guinea-pig small intestine. 1143 87


<< Previous 1 2 3 Next >>