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Galanin Receptors

Galanin is a 30 amino acid non-amidated peptide in humans and identified in 14 other species as a 29 amino acid C-terminally amidated peptide. Galanin is widely distributed in both the central and peripheral nervous systems and the endocrine system. Galanin's wide spectrum of biological activities makes the galaninergic system a promising target for possible therapeutic intervention in pain signaling, cognitive decline, neuroprotection, feeding behavior and controlling insulin release. Galanin affects the release and postsynaptic action of classical neurotransmitters like acetylcholine, norepinephrine, serotonin and dopamine. Galanin co-exists with other neuropeptides, like neuropeptide Y, substance P and vasoactive intestinal peptide, and has been shown to modulate their release and activity. In addition to these actions galanin has more recently been shown to play a trophic and cell survival role to both central and peripheral neurons, implying a role in stroke, brain injury/disease and peripheral neuropathy.

Galanin is a strongly inhibitory, hyperpolarizing peptide, which reduces the excitability of its target cells. Galanin acting at the three galanin receptors opens ATP-sensitive potassium channels, closes calcium channels (N- and L-types), modifies intracellular calcium levels, reduces the stimulatory effect of muscarinic agonists on phospholipase C and modulates the activity of adenylyl cyclase.

Transgenic mice with a disrupted or overexpressing galanin gene have been generated (GalKO, GalOE, respectively). Abnormalities in lactation, pituitary responsiveness to estrogen, and peripheral nerve injury, as well as an increased ability to develop status epilepticus have been described in galanin deficient animals. Animals overexpressing galanin in the central and/or peripheral nervous systems demonstrate suppression of nociception and neuropathic pain behavior, seizure development, a reduction in hippocampal cell death after excitotoxic damage as well as suppressed hippocampal excitability and cognitive deficits.

The diverse physiological effects of galanin are mediated via three G protein-coupled receptors; GalR1-3, which have been cloned from several species (human, rat, mouse), showing only 40-60 % amino acid identity.

GalR1 is localized mainly in the hypothalamus, the hippocampus and the spinal cord, and is negatively coupled to adenylyl cyclase through Gi/Go proteins. GalR2 has been cloned from rat hypothalamus, rat dorsal root ganglia, human placenta, human DNA library and from mouse brain; Unlike GALR1 and GALR3, GALR2 positively couples to phospholipase C mediated via Gq/11 and hence activates the MAP kinase pathways (ERK). It is activated by galanin (2-11), galanin (2-29) and [D-Trp2]-galanin. GalR3 was cloned from rat hypothalamus and is localized mainly in the heart, spleen and testis; it recognizes galanin (2-29) as specific ligand. GalR3 couples to Gi/Go proteins and mediates opening of G protein-coupled inward-rectifying potassium channels (GIRK).

Several peptide type chimeric galanin receptor ligands, M15 (Galantide), M32, M35, M40 and C7, have been synthesized. These can act as galanin receptor antagonists in numerous situations in vivo. Further, these chimeric ligands act often as full or partial agonists in vitro to all three galanin receptors when expressed in various stably transfected cell lines.

Five types of low MW galanin receptor ligands have been reported. A fungal metabolite SCH-202596 (IC50 of 1.7 µM at hGALR1), a series of dithiin-1,1,4,4-tetroxide derivatives that are GalR1 antagonists with submicromolar affinity; galnon, a low molecular weight tripeptidomimetic agonist (Ki of 3-8 mM), which is equally active against all three receptor subtypes and is systemically active and affects appetite, seizures and pain; and galmic, identified from a small synthetic scaffold library with a Ki = 34.2 mM for GalR1. Galmic suppresses long-term potentiation in the dentate gyrus; blocks status epilepticus (i.hc or i.p.); shows antidepressant-like effects in the forced-swim test (i.p.), and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. Finally, N4-[3-(benzyloxy)phenyl]-2-[4-(2-fluorophenyl)-1-piperazinyl]-N6,N6-dimethyl-4,6-pyrimidinediamine has been reported as a 20 nM GalR3 specific ligand with antidepressant activity.

Galanin-Like Peptide, GALP, a 60 amino acid neuropeptide isolated from porcine hypothalamus. contains the non-variable 1-13 amino acids of galanin between positions 9 and 21. GALP binds GALR1 and GALR2 but neither receptor is thought to mediate the endogenous actions of GALP since the peptide retains biological activity in GALR1 or GALR2 knock-out animals.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently
Accepted
Name
GalR1 GalR2 GalR3
Alternative
Name
Galanin receptor type 1 Galanin receptor type 2 Galanin receptor type 3
Structural
Information
349 aa (human) 372 aa (rat) 370 aa (rat)
Agonists Galanin (G0278 (h), G5773 (p), G8272 (r))
Galanin (1-16)
GALP (G8041)
Galnon, galmic
Galanin (G0278 (h), G5773 (p), G8272 (r))
Galanin (2-16)
Galanin (2-11) (G8293 (p,r))
GALP (G8041)
Galanin (G0278 (h), G5773 (p), G8272 (r))
Galanin(2-29)
N4-[3-(Benzyloxy)phenyl]-2-[4-
(2-fluorophenyl)-1-piperazinyl]-
N6,N6-dimethyl-4,6-pyrimidinediamine
Antagonists M15 (Galantide) (G1278)
M35
M40
C7
M32 (G8165)
[D-Thr6,D-Trp8,9,(1-15)ol Galanin fragment 1-15
[D-Trp8,9]-Galanin(1-15)ol
SCH-202596
Dithiin-1,1,4,4-tetroxide
M15 (Galantide) (G1278)
M35
M40
C7
M32 (G8165)
[D-Thr6,D-Trp8,9,(1-15)ol Galanin fragment 1-15
[D-Trp8,9]-Galanin(1-15)ol
M15 (Galantide) (G1278)
M35
M40
C7
M32 (G8165)
[D-Thr6,D-Trp8,9,(1-15)ol Galanin fragment 1-15
[D-Trp8,9]-Galanin(1-15)ol
Signal
Transduction
Mechanisms
Gi/o (cAMP modulation) Gq/11 (increase IP3/DAG) Gi/o (GIRK modulation)
Radioligands
of Choice
[125I]-Galanin, porcine, human, rat [125I]-Galanin, porcine, human, rat [125I]-Galanin, porcine, human, rat
Tissue
Expression
Hypothalamus, Amygdala, Hippocampus,
Thalamus brainstem, Spinal cord, DRG,
Heart, Lung, Kidney, Testis
Cortex, Hypothalamus, Hippocampus
Amygdala, Cerebellum, DRG, Heart
Liver, Lung, Kidney, Intestine,
Uterus, Ovary, Stomach, Pancreas,
Testis
Hypothalamus, Pituitary, Medulla
Cerebral cortex, Cerebellum, DRG,
Olfactory bulb, Spinal cord,
Heart, Spleen, Testis, Liver,
Stomach, Lung, Kidney
Physiological
Function*
Glu ↓
NE ↑
5-HT ↓
SP release ↓
Cholinergic neuron survival ↑
Ach ↓
Insulin release ↓
Cholinergic neuron survival ↑
Ach ↑↓
NE ↑
GH ↑
Modification of leptin
NPY
Dopamine response
GH ↑
Modification of leptin
NPY
Dopamine response
Disease
Relevance*
Anticonvulsanti
Ischemia
Analgesia
Allodynia
Alzheimer’s disease
Cognitive enhancer
Alzheimer’s disease
Cognitive enhancer
Dwarfism
Feeding disorders
Anticonvulsant
Antidepressant
Neuroprotection
Dwarfism
Feeding disorders
Depression
Antidepressant

 

Footnotes

* The relevance overlaps between GalR subtypes

 

Abbreviations

Ach: Acetylcholine
C7: Galanin (1-13)-spantide amide
DA: Dopamine
DRG: Dorsal root ganglion
GALP: Galanin-Like Peptide
GH: Growth hormone
Glu: Glutamate
5-HT: Ser
M15: Galanin (1-13)-substance P (5-11) amide
M32: Galanin (1-13)-neuropeptide Y (25-36) amide
M35: Galanin (1-13)-bradykinin (2-9) amide
M40: Galanin (1-13)-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide
NE: Norepinephrine
SCH-202596: Spirocoumaranon
SP: Substance P

h: human
p: porcine
r: rat

 

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References