Galanin receptors as a potential target for neurological disease

Freimann, Krista; Kurrikoff, Kaido; Langel, Ülo

doi:10.1517/14728222.2015.1072513

Cited by 20 publications

(15 citation statements)

References 146 publications

(115 reference statements)

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“…Galanin is also thought to be involved in several chronic diseases associated with aging yet no link has been previously established with osteoporosis. Since galanin receptor blockers are currently tested for a variety of indications, including addiction, pain, and epilepsy (9,55), the information provided here that they may also affect bone metabolism is of potential clinical importance and may shed some light on these medically relevant questions.…”

Section: Discussionmentioning

confidence: 99%

Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent

Idelevich¹,

Sato²,

Nagano³

et al. 2018

Journal of Clinical Investigation

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In the brain, the ventral hypothalamus (VHT) regulates energy and bone metabolism. Whether this regulation uses the same or different neuronal circuits is unknown. Alteration of AP1 signaling in the VHT increases energy expenditure, glucose utilization, and bone density, yet the specific neurons responsible for each or all of these phenotypes are not identified. Using neuron-specific, genetically targeted AP1 alterations as a tool in adult mice, we found that agouti-related peptide-expressing (AgRP-expressing) or proopiomelanocortin-expressing (POMC-expressing) neurons, predominantly present in the arcuate nucleus (ARC) within the VHT, stimulate whole-body energy expenditure, glucose utilization, and bone formation and density, although their effects on bone resorption differed. In contrast, AP1 alterations in steroidogenic factor 1-expressing (SF1-expressing) neurons, present in the ventromedial hypothalamus (VMH), increase energy but decrease bone density, suggesting that these effects are independent. Altered AP1 signaling also increased the level of the neuromediator galanin in the hypothalamus. Global galanin deletion (VHT galanin silencing using shRNA) or pharmacological galanin receptor blockade counteracted the observed effects on energy and bone. Thus, AP1 antagonism reveals that AgRP- and POMC-expressing neurons can stimulate body metabolism and increase bone density, with galanin acting as a central downstream effector. The results obtained with SF1-expressing neurons, however, indicate that bone homeostasis is not always dictated by the global energy status, and vice versa.

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Section: Discussionmentioning

confidence: 99%

Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent

Idelevich¹,

Sato²,

Nagano³

et al. 2018

Journal of Clinical Investigation

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show abstract

“…Neuropeptides and their receptors play a crucial role in maintaining the homeostasis of the human nervous system and in maintaining health (Freimann et al, 2016, Davidson et al, 2011). Neuropeptides such as galanin play critical roles in inflammation (Pinter et al, 2013), mood, appetite and alcohol intake and their mis-expression has been associated with inflammatory pain, depression, alcohol abuse and obesity (Lang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome

et al. 2017

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We have successfully used comparative genomics to identify putative regulatory elements within the human genome that contribute to the tissue specific expression of neuropeptides such as galanin and receptors such as CB1. However, a previous inability to rapidly delete these elements from the mouse genome has prevented optimal assessment of their function in-vivo. This has been solved using CAS9/CRISPR genome editing technology which uses a bacterial endonuclease called CAS9 that, in combination with specifically designed guide RNA (gRNA) molecules, cuts specific regions of the mouse genome. However, reports of “off target” effects, whereby the CAS9 endonuclease is able to cut sites other than those targeted, limits the appeal of this technology. We used cytoplasmic microinjection of gRNA and CAS9 mRNA into 1-cell mouse embryos to rapidly generate enhancer knockout mouse lines. The current study describes our analysis of the genomes of these enhancer knockout lines to detect possible off-target effects. Bioinformatic analysis was used to identify the most likely putative off-target sites and to design PCR primers that would amplify these sequences from genomic DNA of founder enhancer deletion mouse lines. Amplified DNA was then sequenced and blasted against the mouse genome sequence to detect off-target effects. Using this approach we were unable to detect any evidence of off-target effects in the genomes of three founder lines using any of the four gRNAs used in the analysis. This study suggests that the problem of off-target effects in transgenic mice have been exaggerated and that CAS9/CRISPR represents a highly effective and accurate method of deleting putative neuropeptide gene enhancer sequences from the mouse genome.

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“…Galanin, a multifunctional neuropeptide expressed in various cell types of the CNS, contributes to neuroendocrine function, learning and memory, mood, nociception, and appetite (4,5). The diverse actions of galanin are mediated by three GPCR subtypes (GalR1, GalR2, and GalR3), which show unique distribution profiles in the brain and trigger distinct intracellular pathways (6). In rodent models, centrally administered galanin blocks the rewarding effects of morphine (7), whereas administration of galanin-like molecules attenuates symptoms of morphine withdrawal (8).…”

Section: Galanin System and Pharmacological Responses To Opioid Alkalmentioning

confidence: 99%

Opioid–galanin receptor heteromers differentiate the dopaminergic effects of morphine and methadone

Serafini¹,

Zachariou²

2019

Journal of Clinical Investigation

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Galanin receptors as a potential target for neurological disease

Abstract: Recent advances and novel approaches in migrating the directions of subtype-selective ligand development and chemical modifications of the peptide backbone highlight the importance of the galanin neurochemical system as a potential target for drug development.

Cited by 20 publications

References 146 publications

Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent

Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent

An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome

Opioid–galanin receptor heteromers differentiate the dopaminergic effects of morphine and methadone

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