Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels

Ainscow, Edward; Mirshamsi, Shirin; Tang, Teresa; Ashford, M. L. J.; Rutter, Guy A.

doi:10.1111/j..2002.00429.x

Cited by 19 publications

(32 citation statements)

References 27 publications

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“…26). Although ATP-sensitive K ϩ channels may mediate these responses, no changes in ATP concentrations were detected (27). An alternative hypothesis is that SGLTs mediate the change in membrane potential, and this is supported by the observations that phlorizin increases food intake when injected into the cerebrospinal fluid (28,29) and blocks the glucose-mediated increase in firing rate of glucose-responsive neurons in the hypothalamus (30).…”

Section: Discussionmentioning

confidence: 99%

A glucose sensor hiding in a family of transporters

Dı́ez-Sampedro

Hirayama

Osswald

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

286

275

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We have examined the expression and function of a previously undescribed human member (SGLT3͞SLC5A4) of the sodium͞glu-cose cotransporter gene family (SLC5) that was first identified by the chromosome 22 genome project. The cDNA was cloned and sequenced, confirming that the gene coded for a 659-residue protein with 70% amino acid identity to the human SGLT1. RT-PCR and Western blotting showed that the gene was transcribed and mRNA was translated in human skeletal muscle and small intestine. Immunofluorescence microscopy indicated that in the small intestine the protein was expressed in cholinergic neurons in the submucosal and myenteric plexuses, but not in enterocytes. In skeletal muscle SGLT3 immunoreactivity colocalized with the nicotinic acetylcholine receptor. Functional studies using the Xenopus laevis oocyte expression system showed that hSGLT3 was incapable of sugar transport, even though SGLT3 was efficiently inserted into the plasma membrane. Electrophysiological assays revealed that glucose caused a specific, phlorizin-sensitive, Na ؉ -dependent depolarization of the membrane potential. Uptake assays under voltage clamp showed that the glucose-induced inward currents were not accompanied by glucose transport. We suggest that SGLT3 is not a Na ؉ ͞glucose cotransporter but instead a glucose sensor in the plasma membrane of cholinergic neurons, skeletal muscle, and other tissues. This points to an unexpected role of glucose and SLC5 proteins in physiology, and highlights the importance of determining the tissue expression and function of new members of gene families.Na͞sugar cotransporter ͉ human SGLT3 ͉ muscle

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Section: Discussionmentioning

confidence: 99%

A glucose sensor hiding in a family of transporters

Dı́ez-Sampedro

Hirayama

Osswald

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

286

275

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“…Consequently, closure of K ATP channels and increased electrical activity in response to elevated glucose concentrations have also been identified in a population of hypothalamic GE neurones (Ashford et al 1990;Spanswick et al 1997;Song et al 2001). Of note, the closure of K ATP channels may also involve increased release of lactate from neighbouring glial cells as glucose concentrations rise, followed by an increase in the conversion of lactate to pyruvate in GE neurones (Ainscow et al 2002;Lam et al 2005). Importantly, levels of the lactate/monocarboxylate transporter MCT-1, which are very low in pancreatic β-cells (Sekine et al 1994;Ishihara et al 1999;Cohen et al 2001), appear to be relatively high in the hypothalamus (Ainscow et al 2002), and may allow lactate to serve as a regulator of GE (or GI) neurones.…”

Section: Mechanisms Of Glucose Detection By Hypothalamic Glucose-sensmentioning

confidence: 99%

“…1) of the hypothalamus means that they are in close association with the median eminence, a region where the blood-brain barrier is more permeable than usual owing to a highly vascularized local capillary network (Ganong, 2000). These specialist hypothalamic neurones might therefore be exposed to higher glucose concentrations than neurones in deeper brain regions (Spanswick et al 1997;Ganong, 2000;Mobbs et al 2001;Ainscow et al 2002;Fioramonti et al 2004). The likely involvement of glucokinase (GK) in hypothalamic glucose sensing (Dunn-Meynell et al 2002) might also indicate that glucose-sensing neurones are exposed to higher glucose concentrations than other brain areas, given that the K m for glucose of this enzyme is 8-15 mmol l −1 (Matschinsky et al 1998;Roncero et al 2000).…”

Section: Glucose Sensitivity Of Hypothalamic Glucose-sensing Neuronesmentioning

confidence: 99%

“…Of note, the closure of K ATP channels may also involve increased release of lactate from neighbouring glial cells as glucose concentrations rise, followed by an increase in the conversion of lactate to pyruvate in GE neurones (Ainscow et al 2002;Lam et al 2005). Importantly, levels of the lactate/monocarboxylate transporter MCT-1, which are very low in pancreatic β-cells (Sekine et al 1994;Ishihara et al 1999;Cohen et al 2001), appear to be relatively high in the hypothalamus (Ainscow et al 2002), and may allow lactate to serve as a regulator of GE (or GI) neurones. Nevertheless, careful analysis of the levels of MCT-1 expression at the level of individual neurones in this brain region, and correlation with responses to glucose and/or lactate, has yet to be performed.…”

Section: Mechanisms Of Glucose Detection By Hypothalamic Glucose-sensmentioning

confidence: 99%

“…Recent studies have suggested that a further population of GE neurones may sense glucose independently of changes in K ATP channel activity. Thus, glucose-induced increases in intracellular free ATP concentrations are considerably smaller in hypothalamic neurones than in pancreatic β-cells (Ainscow et al 2002), complicating the proposed role of changes in K ATP channel activity in GE neurones. Furthermore, a K ATP channel-independent glucose-sensing mechanism has been identified in a population of ARC GE neurones (Fioramonti et al 2004), which is proposed to involve cell depolarization resulting from the opening of a non-specific cation channel at elevated glucose concentrations.…”

Section: Mechanisms Of Glucose Detection By Hypothalamic Glucose-sensmentioning

confidence: 99%

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Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?

Mountjoy

Rutter

2007

Experimental Physiology

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A fuller understanding of the central mechanisms involved in controlling food intake and metabolism is likely to be crucial for developing treatments to combat the growing problem of obesity in Westernised societies. Within the hypothalamus, specialized neurones respond to both appetite-regulating hormones and circulating metabolites to regulate feeding behaviour accordingly. Thus, the activity of hypothalamic glucose-excited and glucose-inhibited neurones is increased or decreased, respectively, by an increase in local glucose concentration. These 'glucosesensing' neurones may therefore play a key role in the central regulation of food intake and potentially in the regulation of blood glucose concentrations. Whilst the intracellular signalling mechanisms through which glucose-sensing neurones detect changes in the concentration of the sugar have been investigated quite extensively, many elements remain poorly understood. Furthermore, the similarities, or otherwise, with other nutrient-sensing cells, including pancreatic islet cells, are not completely resolved. In this review, we discuss recent advances in this field and explore the potential involvement of AMP-activated protein kinase and other nutrient-regulated protein kinases.

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Defining pathways of loss and secretion of chemical messengers from astrocytes

Evanko

Zhang

Zorec

et al. 2004

Glia

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It is becoming evident that glia, and astrocytes in particular, are intimately involved in neuronal signaling. Astrocytic modulation of signaling in neurons appears to be mediated by the release of neuroactive compounds such as the excitatory amino acid glutamate. Release of these transmitters appears to be driven by two different processes: (1) a volume regulatory response triggered by hypo-osmotic conditions that leads to the release of osmotically active solutes from the cytoplasm into the extracellular space, and (2) intracellular calcium-dependent vesicle-mediated excytotic release. The regulatory volume decrease may be mediated by any of several different pathways that increase membrane permeability, thus allowing osmolytes to travel down their concentration gradient into the extracellular space. Such pathways include anion channels, hemichannels, P2X receptor channels, and transporters or multidrug resistance proteins. The excytotic release process may use calcium triggered synaptic like vesicle fusion or alterations in constitutive vesicle trafficking to the membrane. Determining the contribution of any of these release mechanisms requires agents that can be used to specifically block pathways of interest. Currently, many of the pharmacological compounds being used exhibit a great deal of cross-reactivity between several of these pathways. For example, the popular anion channel inhibitor 5-nitro-2-(3-phenyl-propylamino)benzoic acid (NPPB) is an efficient blocker of both hemichannels and vesicle loading. This demonstrates the need to more fully characterize the activities of the agents currently available and to choose pathway blockers carefully when designing experiments.

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Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels

Cited by 19 publications

References 27 publications

A glucose sensor hiding in a family of transporters

A glucose sensor hiding in a family of transporters

Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?

Defining pathways of loss and secretion of chemical messengers from astrocytes

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