Glucose increases intracellular free Ca²⁺ in tanycytes via ATP released through connexin 43 hemichannels

Abstract

The ventromedial hypothalamus is involved in regulating feeding and satiety behavior, and its neurons interact with specialized ependymal-glial cells, termed tanycytes. The latter express glucose-sensing proteins, including glucose transporter 2, glucokinase and ATP-sensitive K+ (KATP) channels, suggesting their involvement in hypothalamic glucosensing. Here, the transduction mechanism involved in the glucose-induced rise of intracellular free Ca2+ concentration ([Ca2+]i) in cultured β-tanycytes was examined. Fura-2AM time-lapse fluorescence images revealed that glucose increases the intracellular Ca2+ signal in a concentration-dependent manner. Glucose transportation, primarily via glucose transporters, and metabolism via anaerobic glycolysis increased connexin43 (Cx43) hemichannel activity, evaluated by ethidium uptake and whole cell patch clamp recordings, through a KATP channel-dependent pathway. Consequently, ATP export to the extracellular milieu was enhanced, resulting in activation of purinergic P2Y1 receptors followed by inositol trisphosphate receptor activation and Ca2+ release from intracellular stores. The present study identifies the mechanism by which glucose increases [Ca2+]i in tanycytes. It also establishes that Cx43 hemichannels can be rapidly activated under physiological conditions by the sequential activation of glucosensing proteins in normal tanycytes.

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…These findings are in line with growing literature showing that hypothalamic glial cells are involved in central glucose sensing and action (25)(26)(27)(28)(29). It is important to mention that we did not observe an increase in palmitate oxidation in response to AICAR in cortical astrocytes.…”

“…Hypothalamic neurons (24) and glia (25)(26)(27)(28)(29) are both able to sense glucose, and the importance of astroglia in central nutrient sensing has been recently emphasized (30). It is unclear if glucose modulation of LCFACoA metabolism occurs in neurons and/or astrocytes and whether or not such a feature distinguishes hypothalamic nuclei from other brain regions.…”

Typical and atypical stem cells in the brain, vitamin C effect and neuropathology

“…Tanycytes play a major role in the formation of the median eminence-cerebrospinal fl uid barrier ( Figure 2E). More recently, these cells have been found to be crucial for the brain glucose sensing mechanism (Cortes-Campos et al, 2011;Orellana et al, 2012).…”

Monocarboxylate Transporters (MCTs) and their Role in Hypothalamic Glucosensing

“…Therefore, the presence of MCT1 and MCT4 in tanycytic basal processes and MCT2 expression in AN neurons suggest that lactate could be transferred between both cellular types as a signal derived from glucose for regulating energy balance and food intake. In support of this model, it has been demonstrated that glucose increases intracellular Ca 2+ concentration ([Ca 2+ ] i ) in cultured tanycytes, a response that is oxidative phosphorylation-independent but can be diminished through the inhibition of glucokinase, a critical glucosensor enzyme expressed in tanycytes [32][33][34]. Interestingly, this mechanism involves the opening of hemi channels (HC), and pharmacological inhibitors of HC abolish the response to glucose, but do not affect the efflux of lactate [6,33,35].…”

“…In support of this model, it has been demonstrated that glucose increases intracellular Ca 2+ concentration ([Ca 2+ ] i ) in cultured tanycytes, a response that is oxidative phosphorylation-independent but can be diminished through the inhibition of glucokinase, a critical glucosensor enzyme expressed in tanycytes [32][33][34]. Interestingly, this mechanism involves the opening of hemi channels (HC), and pharmacological inhibitors of HC abolish the response to glucose, but do not affect the efflux of lactate [6,33,35]. Several studies have shown that ICV administration of lactate decreases food intake and stimulates pancreatic insulin secretion [36,37].…”