Ghrelin modulates electrical activity of area postrema neurons

Abstract

Ghrelin, a peptide hormone secreted from the stomach, is known to have a potent appetite-stimulating activity. Recently, it has been shown that area postrema (AP), a caudal brain stem center that lacks a blood-brain barrier, is a key site of activity for ghrelin in stimulating appetite and regulating pancreatic protein secretion. In this study, we have examined the ability of ghrelin to regulate the electrical activity of area postrema neurons using patch-clamp electrophysiology. Using current-clamp configuration, we found that at a concentration of 10 nM, ghrelin caused inhibition in 19% of neurons tested, while a further 19% were excited by similar application of ghrelin. The remaining 62% of AP neurons were insensitive to ghrelin. These effects were concentration dependent, with an apparent EC 50 of 1.9 nM. Voltage-clamp recordings revealed that ghrelin caused a potentiation of voltage-gated K ϩ currents in neurons that exhibited a hyperpolarization and a potentiation of a depolarizing nonspecific cation current (NSCC) in those neurons that exhibited a depolarization of membrane potential. These are the first data showing that ghrelin exerts a direct effect on electrical activity of AP neurons and supports the notion that ghrelin can act via the AP to regulate energy homeostasis. patch clamp; action potential; sensory circumventricular organ; energy homeostasis GHRELIN IS AN ACYLATED 28-amino acid peptide hormone, which was discovered on the basis of its activity as an endogenous ligand for the growth hormone secretagogue receptor (GHSR) (35). Originally isolated from the stomach, ghrelin has also been shown to be expressed in various tissues, including the duodenum, adrenal gland, lung, and gonads (22), as well as in neurons in the hypothalamus (11). In addition to its role in the stimulation of growth hormone release in the pituitary, ghrelin is thought to play several roles in the regulation of energy balance. Circulating levels of ghrelin are increased in the fasting state and in anticipation of food (2, 12, 13). Conversely, ghrelin levels are attenuated by feeding and the presence of nutrients in the stomach (58), or by treatment with leptin (2). Administration of ghrelin potently stimulates food intake in rats (58, 64, 65), mice (2), and humans (63). These studies suggest a physiological role in initiation of feeding. Ghrelin is also suggested to play a role in long-term regulation of energy balance, as chronic administration of ghrelin causes weight gain by reducing fat utilization as an energy source (58). Lastly, ghrelin also plays a role in the digestion of food and the stimulation of gastric motility, acid secretion, and pancreatic protein secretion (38, 41).There is considerable interest as to the mechanism by which ghrelin exerts its appetite-stimulating effects, and, in particular, the site of action of ghrelin in the central nervous system (CNS). For example, the neuropeptide Y/Agouti-related peptide (NPY/AGRP) neurons within the arcuate nucleus of the hypothalamus (ARC) are suggested by many t...

Prokineticin 2 modulates the excitability of area postrema neurons in vitro in the rat

“…PK2 was also shown to influence AP cells in a concentration-dependent manner, with an apparent EC 50 that falls between previously identified EC 50 values for PK2 of 2.3 and 63 pM in the paraventricular nucleus and SFO, respectively (6,48). Similarly, other peptides that have been shown to influence AP neuronal activity have also been reported to exert depolarizing and hyperpolarizing effects on different subpopulations of AP cells (9,10,46,47). Our findings with PK2 indicate that the differential responsiveness of separate populations of AP neurons is most likely associated with the separate roles of these neurons in the regulation of integrated autonomic outputs.…”

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

“…Rats with lesions in the area postrema, a caudal brain stem center devoid of blood-brain barrier, did not respond to peripheral acyl ghrelin-induced stimulation of food intake (Gilg and Lutz, 2006). A recent patch-clamp electrophysiological study showed that acyl ghrelin exerted a direct effect on electrical activity of neurons in the area postrema, another brain region lacking the blood-brain barrier, supporting the notion that acyl ghrelin could act via the area postrema to regulate feeding and energy homeostasis (Fry and Ferguson, 2009). In addition, electrophysiological recordings found that acyl ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus, revealing that release of acyl ghrelin at the arcuate nucleus and hypothalamic paraventricular nucleus might stimulate the release of orexigenic peptides and neurotransmitters, thus representing a regulatory circuit controlling energy homeostasis (Cowley et al, 2003).…”

Investigation of the presence of ghrelin in the central nervous system of the rat and mouse

“…Receptor localization has been shown by in situ hybridization in rats, mice, and lemurs (Guan et al, 1997;Mitchell et al, 2001;Zigman et al, 2006;Andrews et al, 2008Andrews et al, , 2009Ferens et al, 2010a,b). Moreover, ghrelin and other specific agonists for ghrelin receptors have direct actions on neurons in the brain and spinal cord (Nakazato et al, 2001;Cowley et al, 2003;Lin et al, 2004;Shimizu et al, 2006;Fry and Ferguson, 2009;Ferens et al, 2010a).…”