Cloning and Expression of the Human Galanin Receptor GalR2

Neuropeptides like galanin produced and released by small cell lung cancer (SCLC) cells are considered principal mitogens in these tumors. We identi®ed the galanin receptor type 2 (GALR2) as the only galanin receptor expressed in H69 and H510 cells. Photoa nity 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 Ca 2+ 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 PKCinhibitor GF109203X had no e ect on galanin-dependent ERK activity. A rise of the intracellular calcium concentration was necessary and su cient 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 Ga S -Ga i protein. In H69 cells, galanin activated the monomeric GTPase RhoA and induced stress ®ber formation in Swiss 3T3 cells expressing GALR2. Thus, we provide the ®rst 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.

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“…The cloned GALR2 cDNA sequence was identical to the one recently isolated from human small intestine (Bloomquist et al, 1998).…”

Section: Photoaffinity Labeling Of Galanin-activated G-proteins In H6mentioning

confidence: 81%

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

et al. 2000

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“…N-terminal truncation of Gly 1 reduces the affinity of GAL 1 for galanin in comparison with GAL 2 and GAL 3 , a finding that led to the introduction of the galanin fragment (2-11) (also known as AR-M1896) as a "non-GAL 1 " galanin receptor ligand that was only able to activate GAL 2 and GAL 3 (Liu et al, 2001;Lu et al, 2005b). Although removal of further N-terminal amino acids from galanin (2-11) resulted in a loss of affinity for all three receptors in cell lines transfected with galanin receptors (Wang et al, 1997b;Bloomquist et al, 1998;Smith et al, 1998), the fragment galanin is fully active in the anterior pituitary in vivo (Wynick et al, 1993;Kinney et al, 1998;Todd et al, 2000).…”

Section: Galanin Receptor-ligand Interactionsmentioning

confidence: 99%

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

et al. 2014

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“…Three galanin receptors have been identified and cloned (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and all of the three subtype mRNAs are expressed within DRGs and spinal cord with different distribution patterns, expression levels, and response to peripheral nerve injury (4,(34)(35)(36)(37)(38). All three known receptors belong to the superfamily of G protein-coupled transmembrane receptors, and they use different transduction signaling pathways (see ref.…”

mentioning

confidence: 99%

Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: Selective actions via GalR1 and GalR2 receptors

Liu

Brumovsky

Schmidt

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

208

156

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Galanin is a 29-aa neuropeptide with a complex role in pain processing. Several galanin receptor subtypes are present in dorsal root ganglia and spinal cord with a differential distribution. Here, we describe a generation of a specific galanin R2 (GalR2) agonist, AR-M1896, and its application in studies of a rat neuropathic pain model (Bennett). The results show that in normal rats mechanical and cold allodynia of the hindpaw are induced after intrathecal infusion of low-dose galanin (25 ng per 0.5 l͞h). The same effect is seen with equimolar doses of AR-M1896 or AR-M961, an agonist both at GalR1 and GalR2 receptors. In allodynic Bennett model rats, the mechanical threshold increased dose-dependently after intrathecal injection of a high dose of AR-M961, whereas no effect was observed in the control or AR-M1896 group. No effect of either of the two compounds was observed in nonallodynic Bennett model rats. These data indicate that a low dose of galanin has a nociceptive role at the spinal cord level mediated by GalR2 receptors, whereas the antiallodynic effect of high-dose galanin on neuropathic pain is mediated by the GalR1 receptors. Thus, a selective GalR1 agonist may be used to treat neuropathic pain.alanin is a 29-aa (30 aa in humans) neuropeptide (1). It has a wide distribution in the nervous system and may be involved in a variety of physiological and pathophysiological activities (2), including pain signaling (3-5). Galanin is upregulated in dorsal root ganglion (DRG) neurons in many animal models based on peripheral nerve injury, including complete axotomy (6, 7), complete nerve constriction injury (8-10), as well as partial nerve ligation (9, 10). In agreement, enhanced immunoreactive galanin release was also found in the superficial dorsal horn ipsilateral to sciatic nerve injury (11).Galanin's role in pain signaling is complex, and early studies revealed inhibitory (12-15) and at low doses excitatory (16-18) effects of galanin, as well as enhanced inhibition after nerve injury (17,19). It also has been proposed that galanin after nerve injury may contribute to neuropathic pain (9), and recently infusion of low doses of galanin resulted in a decrease in pain threshold (20,21).Three galanin receptors have been identified and cloned (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and all of the three subtype mRNAs are expressed within DRGs and spinal cord with different distribution patterns, expression levels, and response to peripheral nerve injury (4, 34-38). All three known receptors belong to the superfamily of G protein-coupled transmembrane receptors, and they use different transduction signaling pathways (see ref. 34). The multitude of receptors may at least in part underlie the diversity and opposing views on the apparent functional roles of galanin in pain processing at the spinal level.A problem in the field has been the lack of specific and efficient drugs affecting galaninergic mechanisms. However, Bartfai and colleagues (39) ]Gal(1-16)-NH 2 , which has high affinity and functional a...

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Cloning and Expression of the Human Galanin Receptor GalR2

Cited by 63 publications

References 23 publications

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: Selective actions via GalR1 and GalR2 receptors

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