calpain inhibitor 1 Ghsr may have therapeutic value in disor
Ghsr may have therapeutic value in disorders associated with impairments in AHN. As anxiety disorders and enhanced fear responses observed in PTSD are linked with overgeneralization of similar but distinct memories (i.e poor discrimination), we suggest that acyl-ghrelin’s anti-anxiety effect (Lutter et al., 2008) may, at least in part, be mediated by promoting AHN. Indeed, this is consistent with recent findings that the action of the P7C3 anti-depressant is dependent upon Ghsr mediated AHN (Walker et al., 2014). In addition, as AHN undergoes age-related decline and is aberrant in pre-clinical models of neurodegenerative diseases such as Alzheimer’s (Komuro et al., 2015) and Parkinson’s disease (Höglinger et al., 2004), activation of the ghrelin/Ghsr axis may be of therapeutic value in alleviating cognitive decline and promoting healthy ageing. Moreover, as diets high in fat reduce neurogenesis (Lindqvist et al., 2006) and impair cognition (Erion et al., 2014), our data suggest that this may be due, at least in part, to the well described reduction in circulating acyl-ghrelin by high fat diet (Tschöp et al., 2001). Interestingly, data has emerged suggesting the presence of a hypothalamic neurogenic zone that may regulate energy balance (for a review see (Rojczyk-Gołȩbiewska et al., 2014)). Given the role of ghrelin in regulating orexigenic neurons in this region (Cowley et al., 2003), studies are warranted to investigate whether the peptide modulates new neuron formation in the hypothalamus.
Conflict of interest
Acknowledgments We would like to thank Drs James Abbey, Andrei Golovko and Benjamin Morpugo for assistance with study design and Mrs Sally James for assistance with confocal microscopy. This work was funded by grants from the Wales-Texas Initiative, the Medical Research Council (Grant no. G0902250), the St David’s Medical Foundation and The Royal Society to JSD.
Introduction The calpain inhibitor 1 plays an essential role in the regulation of appetite, energy balance, and body weight, and some genetics studies show that obesity is mainly a heritable disorder affecting the neural control of energy homeostasis (O’Rahilly and Farooqi, 2008). CNS receives feedback information from peripheral tissues (in the form of hormones, nutrients, or afferent sensory neural information via the peripheral nervous system) and integrates this information and coordinates output commands to maintain energy balance. Ghrelin (GHRL) is one of metabolic hormone that signals the brain to control energy balance. GHRL is a 28 (mammals)/26 (avian) amino acid peptide predominantly synthesized in the stomach (mammals)/proventriculus (avian), where it is secreted into the circulation. The growth hormone secretagogue receptor (GHSR) is the key receptor through which GHRL and other GH secretagogues mediates these effects (Liu et al., 2007, Shuto et al., 2002). GHSR belongs to the rhodopsin-like family of 7TM receptors, which has seven trans-membrane α-helical domains linked by three intracellular and three extracellular loops. The N- and C-terminal parts are located extra- and intracellularly, respectively. The binding domain for GHRL is located at its extracellular site within both the helical bundle and the extracellular loops, while the signaling effectors interact with the receptor at its intracellular surface (Jeanelle Portelli and Smolders, 2014). The GHSR gene contains two exons and one intron in both mammals and chicken, and its alternative splicing leads to two isoforms; a long variant transcribed into a full-length 7TM receptor (GHSR-1a) and a short, 3′-truncated variant which encodes a 5TM receptor-like protein (GHSR-1b) (Tanaka et al., 2003). The GHSR-1a is produced by the splicing of exon 1 and exon 2 and had normal function, whereas the short variant (GHSR-1b) does not exhibit any binding or functional activity in response to ghrelin (Howard et al., 1996, Tanaka et al., 2003). GHSR-1b acts as a dominant-negative mutant by impairing the cell surface expression of the receptor (Leung et al., 2007). Both GHSR-1a and GHSR-1b can be found in all tissues of chickens, with higher level of GHSR-1a gene in the pituitary, hypothalamus and lower levels in other tissues (Geelissen et al., 2003, Kaiya et al., 2013b, Tanaka et al., 2003).