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Novel heteromeric receptors in gut control:  ghrelin receptors and dopamine receptors working together

We have made the remarkable discovery that ghrelin receptors are involved in control of digestive function not through an action of ghrelin, but through the action of dopamine.

Aims

We will investigate the relevance of our discoveries for treatment of constipation in two disease models.  

Ghrelin is a naturally occurring hormone that had been thought to be a transmitter in the central nervous system (CNS), and some years ago we discovered that ghrelin is a powerful CNS-acting stimulant of defecation in animal models and humans.  A striking conclusion from our discoveries is that the strong stimulation of defecation by ghrelin agonists is independent of ghrelin, which we discovered to be absent from the CNS.  Our data indicate that the physiological activation of the ghrelin receptor, GhrR, is through dopaminergic transmission acting at a combined GhrR / dopamine (DRD2) receptor.  In this project we are investigating how ghrelin and dopamine receptor agonists act and interact at this receptor complex in biophysical systems, isolated cells, native cells and whole animals. 

The nature of the GhrR/DRD2 interaction that we hypothesise from our data and published literature. Biophysical data indicate the receptors form heteromers. Our transfected cell data indicate that dopamine activates G protein coupling to GhrR and a Ca2+ signal, indirectly via DRD2. Our transfected cell data and our in vivo data indicate that both dopamine and ghrelin activation are blocked by a ghrelin receptor antagonist (X). Ghrelin agonism is not blocked by DRD2 antagonism.

References:

Shimizu Y, Chang EC, Shafton AD, Ferens DM, Sanger GJ, Witherington J, Furness JB. Evidence that stimulation of ghrelin receptors in the spinal cord initiates propulsive activity in the colon of the rat. J Physiol (Lond). 2006 Oct 1;576(Pt 1):329–38.

Ellis AG, Zeglinski PT, Brown DJ, Frauman AG, Millard M, Furness JB. Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers. Spinal Cord 2015 Feb;53(2):103–8.

Furness JB, Hunne B, Matsuda N, Yin L, Russo D, Kato I, Fujimiya M, Patterson M, McLeod J, Andrews ZB, Bron R. Investigation of the presence of ghrelin in the central nervous system of the rat and mouse. Neuroscience 2011 Oct 13;193:1–9.

Pustovit RV, Callaghan B, Ringuet MT, Kerr NF, Hunne B, Smyth IM, Pietra C, Furness JB. Evidence that central pathways that mediate defecation utilize ghrelin receptors but do not require endogenous ghrelin. Physiological Reports; 2017 Aug;5(15):e13385.

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