ABSTRACT
The growth hormone (GH) secretagogue receptor (GHS-R1a) is a G protein-coupled receptor (GPCR) expressed in the brain as well as other areas of the body. In the early 1990s, this receptor was expression cloned in MERCK laboratories by using a group of synthesized small molecules known to increase GH release in humans and other animals. Since its discovery, hundreds of studies have shown the importance of this receptor and its endogenous ligand, ghrelin, in metabolism, neurotransmission, and behavior. Even more relevant are the prospective benefits that will result from pharmacologic manipulation of GHS-R1a. Multiple GHS-R1a agonists and antagonists are available for experimentation, and some have been used in patients with promising results. Studies in rodents have revealed intriguing potential roles for GHS-R1a modulation. Our goal in this chapter is to connect these studies with the inherent advantages of targeting this receptor pharmacologically.
Subject(s)
Receptors, Ghrelin/physiology , Animals , Brain/drug effects , Brain/metabolism , Brain/physiology , Ghrelin/metabolism , Ghrelin/pharmacology , Glucose/metabolism , History, 20th Century , History, 21st Century , Homeostasis/drug effects , Homeostasis/genetics , Humans , Obesity/genetics , Obesity/metabolism , Protein Multimerization/genetics , Protein Multimerization/physiology , Receptors, Ghrelin/genetics , Receptors, Ghrelin/history , Receptors, Ghrelin/metabolism , Signal TransductionABSTRACT
Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning.
Subject(s)
Memory Disorders/genetics , Memory Disorders/psychology , Memory/physiology , Receptors, Ghrelin/genetics , Receptors, Ghrelin/physiology , Space Perception/physiology , Animals , Anxiety/psychology , Body Weight/genetics , Body Weight/physiology , Conditioning, Operant/physiology , Fear/psychology , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/physiology , Pain/psychology , Postural Balance/physiology , Reaction Time/physiologyABSTRACT
Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neuroprotection. Furthermore, ghrelin could promote overall health and longevity by acting directly in the immune system and promoting an extended antigen repertoire. The development of mice lacking either ghrelin (ghrelin-/-) or its receptor (ghsr-/-) have provided a valuable tool for determining the relevance of ghrelin and its receptor in these multiple and diverse roles. In this review, we summarize the most important findings and lessons learned from the ghrelin-/- and ghsr-/- mice.
