In part 1 of our ghrelin review, we investigated the discovery of ghrelin and some of its relevant functions. To look into its actions, tissue expression, and the pharmokinetics of similar ligands it is important to get a better idea of its receptor, GHS-R. Ultimately, the effects of ghrelin are incredibly varied and diverse. So much so that is difficult to fully explore its actions. This review will focus mostly on its role on what we know about the receptors themselves
The GHS-R mRNA is expressed as two splice variants encoding the cognate receptor GHS-R1a and the apparently non-functional receptor GHS-R1b. These receptors were identified and characterized after novel experiments exploiting the release of Ca2+ after receptor stimulation (see figure 1). The encoded proteins revealed a seven transmembrane domain receptor, GHSR1a, and a second nonfunctional receptor, GHS-R1b, containing only five transmembrane domains. Both GHS-R1a and GHS-R1b, are encoded by the same gene located on chromosome 3q26.31.
Additionally, the GHS-R1a is conserved among many species, including rat, mouse, chicken, pufferfish, and zebrafish, which is important because most studies that look at the actions of GHS-R1a are performed in rodents.
Ghrelin activation of the ghrelin receptor, GHS-R1a, has many regulatory effects on physiology and behavior, such as enhancement of memory and learning, neuroprotection, immune function improvement, blood glucose control, potentiation of drug and food addiction, and cardiovascular and renal protection.
Another important clinical consideration of this receptor is that GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH (and analogs like sermorelin, CJC, Tesamorelin) increases the binding capacity of 125I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. This is reflected in studies where they dose GHRH with different ghrelin mimics (See figure 2)
The GHS-R1b is a splice variant and a dominant negative form of GHS-R1a. Through various scientific experiments as recently as 2012, it was proposed that GHSR1b prevents GHS-R1a from leaving the ER and regulates its concentration on the plasma membrane. Interestingly, coexpression of both receptors affects GHSR1a dependent calcium signaling, but not ghrelin-induced ERK 1/2 phosphorylation. This is important because it gives us a mechanism by which the receptor and GH secretion can become down-regulated.
In studies where they did pathological and histological quantification of proteins. We are also able to see where most of the GHS-R1a an GHS-R1b are found. GHS-R1a is found most centrally at receptors and the GHS-R1b is found more in periphery such as the skin. The clinical significance of this is not yet clear.
Exciting Possibilities – Heterodimerization
Overall, ghrelin discovery and the work on its’ receptors are all still very new with many new discoveries still being made. The most exciting of which offer better possibilities above and beyond the CJC 1295 and Ipamorelin.
As mentioned in part 1, the GHS-R1a is a G-coupled protein receptor. One newer functionality being discovered is how it can combine with other G-coupled protein receptors to initiate different reactions!
Heterodimerization of the GHS-R1a receptor can happen with the dopamine receptor type 1 (D1R) and type 2 (D2R), as well as the GHS-R1a-MC3 heterodimer. In fact, while studying these two dimers in 2012, the scientists identified another novel heterodimer between the GHS-R1a receptor and the 5-HT2C receptor was identified.
The ability of the GHS-R1a to dimerize with other receptors will likely allow for new treatments that selectively activate only specific di-Ghrelin Receptors 9 mers, and thus, only in certain subsets of neurons. This will modulate signaling in a much more targeted fashion, resulting in a smaller number of negative side effects and more specific therapeutic actions!