Medical information and decision-making in palliative cancer: a qualitative study of patients' perceptions, needs, and preferences regarding physician communication.

Ghrelin is a 28‐amino‐acid peptide that is secreted mainly in the stomach, specifically by the X/A‐like cells []. For the maturation of the active form of ghrelin, the 117‐amino acid precursor undergoes proteolytic processing within the endoplasmic reticulum to form the 28‐amino‐acid peptide known as des‐acyl ghrelin []. Des‐acyl ghrelin is further acylated at Ser3 by the ghrelin O‐acyltransferase enzyme to generate the active form, acyl ghrelin [, ], which we denote as ghrelin thereafter. Ghrelin is expressed in the peripheral tissues, including the gastric mucosa, heart and kidney, as well as the CNS such as the pituitary and hypothalamus [, , , ]. The peripherally produced ghrelin can cross the blood–brain barrier [, , , ] to exert a variety of central effects. Ghrelin has been shown to regulate a myriad of physiological functions including growth hormone secretion [], feeding‐associated behaviors [, , ], glucose homeostasis [], energy balance [], cardiovascular function [], inflammation [], mood [], cognition and Alzheimer's disease [, ], and neuroprotection [], although the underscoring cellular and molecular mechanisms of ghrelin have not been fully elucidated. Ghrelin is the endogenous ligand for the ghrelin hormone secretagogue receptors (GHSRs), which have two isoforms: GHSR‐1α and GHSR‐1β []. GHSR‐1α is the active isoform of the receptors, while GHSR‐1β is the inactive analog. GHSRs (denoting GHSR‐1α thereafter) canonically signal via the Gq proteins, resulting in the activation of PLCβ []. However, the GHSRs can also induce a G‐protein coupling switch from Gq to Gs, leading to the activation of adenylyl cyclase to increase cyclic AMP levels [, ]. This switching is mainly because of the dimerization of GHSR‐1α with the D receptors [, , ]. The GHSRs are expressed in several brain regions including the hypothalamus, substantia nigra, ventral tegmental area and hippocampus [, ]. The dentate gyrus (DG) granule cells (GCs) of the hippocampus express a high density of GHSRs [, ], whereas the roles and underlying mechanisms of ghrelin in DG GCs have not been determined. In the current work, we probed the effects of ghrelin on the excitability of DG GCs and studied the roles of GHSRs in the DG in the modulation of spatial memory. Our results showed that activation of GHSRs excited DG GCs via depression of the G protein‐coupled inwardly rectifying K (GIRK) and ATP‐sensitive K (K) channels and activation of the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels and a persistent Na channel. Microinjection of ghrelin into the DG increased the alternating sequences in the Y maze test, indicating that GHSR‐mediated excitation of DG GCs augmented short‐term spatial memory. Elevation of intracellular cAMP levels and the activity of Exchange Protein directly Activated by cAMP (EPAC) were involved in ghrelin‐mediated excitation of DG GC and augmentation of spatial learning. The procedures and experiments in this study were reviewed and approved by the Institutional Animal Use and Care Committee (IACUC) of the University of North Dakota and were conducted according to the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.