Galanin

Galanin is a is_associated_with::neuropeptide encoded by the GAL is_associated_with::gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three is_associated_with::G protein-coupled receptors.

The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of is_associated_with::action potentials in is_associated_with::neurons. Galanin has been implicated in many biologically diverse functions, including: is_associated_with::nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a is_associated_with::trophic factor. Galanin neurons in the medial preoptic area of the hypothalamus may govern parental behaviour. Galanin is linked to a number of diseases including is_associated_with::Alzheimer's disease, is_associated_with::epilepsy as well as depression, is_associated_with::eating disorders and is_associated_with::cancer. Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon is_associated_with::axotomy in the is_associated_with::peripheral nervous system as well as when seizure activity occurs in the brain. It may also promote is_associated_with::neurogenesis.

Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide and as such inhibits is_associated_with::neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as is_associated_with::acetylcholine, is_associated_with::serotonin, and is_associated_with::norepinephrine, and also with other neuromodulators such as is_associated_with::neuropeptide Y, is_associated_with::substance P, and is_associated_with::vasoactive intestinal peptide.

Discovery
Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine. The structure of galanin was determined in 1983 by the same team, and its is_associated_with::cDNA of galanin was cloned from rat anterior pituitary library in 1987.

Tissue distribution
Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the is_associated_with::hypothalamus, with lower levels in the cortex and is_associated_with::brainstem. Gastrointestinal galanin is most abundant in the is_associated_with::duodenum, with lower concentrations in the stomach, small intestine, and colon.

Structure
Galanin is a is_associated_with::peptide consisting of a chain of 29 is_associated_with::amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as preprogalanin, which is encoded by the GAL gene. The sequence of this gene is highly conserved among mammals, showing over 85% homology between rat, mouse, porcine, bovine, and human sequences. In these animal forms, the first 15 amino acids from the is_associated_with::N-terminus are identical, but amino acids differ at several positions on the is_associated_with::C-terminal end of the protein.

These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced is_associated_with::insulin secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin, and other regulatory peptides, in their autologous species.

The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of preprogalanin. The other two peptides, is_associated_with::galanin-like peptide (GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the preproGALP gene. GALP and alarin are produced by different post-is_associated_with::translational splicing of this gene.

Receptors
Galanin signalling occurs through three classes of receptors, is_associated_with::GALR1, is_associated_with::GALR2, and is_associated_with::GALR3, which are all part of the is_associated_with::G protein-coupled receptor (GPCR) superfamily. Galanin receptors are expressed in the is_associated_with::central nervous system, in the is_associated_with::pancreas, and on is_associated_with::solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons. Experiments into the function of the receptor subtypes involve mostly genetic knockout mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.

Alzheimer's disease
One of the pathological features of the brain in the later stages of is_associated_with::Alzheimer's disease is the presence of overgrown GAL-containing fibres innervating the surviving is_associated_with::cholinergic neurons. Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in post-mortem brains of Alzheimer's patients. The cause and role of this increase is poorly understood.

It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive function in patients by decreasing the amount of is_associated_with::acetylcholine available to these neurons.

A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from is_associated_with::excitotoxic damage and the neurons in the cholinergic basal forebrain from is_associated_with::amyloid toxicity. It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription of factors that promote neuron function and survival. It is still unclear as to whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.

Epilepsy
Galanin in the is_associated_with::hippocampus is an inhibitor of is_associated_with::glutamate but not of is_associated_with::GABA. This means that galanin is capable of increasing the is_associated_with::seizure threshold and, therefore, is expected to act as an is_associated_with::anticonvulsant. To be specific, GalR1 has been linked to the suppression of spontaneous seizures. Agonist antiepileptic drug candidate NAX 5055.

In development
It has been shown that galanin plays a role in the control of the early post-natal is_associated_with::neural development of the is_associated_with::dorsal root ganglion (DRG). Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing is_associated_with::substance P. This suggests that the cell loss by is_associated_with::apoptosis that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.

After injury
In vitro experiments show that DRG cells removed from galanin mutants have impaired abilities to extend is_associated_with::neurites in culture, in that the number of cells producing neurites is decreased by a third and the mean length of these processes was halved when compared to wild-type controls. In vivo, many of the actions of galanin in the brain after an injury are similar to those observed in the developing DRG. Adult mutant animals have been shown to be 35% less capable of regenerating the is_associated_with::sciatic nerve after crush injury, which is linked to long-term functional problems.

Parental role in mice
Galanin-expressing neurons in the medial preoptical area of the brain would be responsible for regulating aggression towards pups by male mice.