Novel calcium-related targets of insulin in hippocampal neurons

Abstract

Both insulin signaling disruption and Ca2+ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca2+-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca2+-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in the brain. Indeed, increasing insulin signaling in the brain via intranasal delivery has yielded promising results such as improving memory in both clinical and animal studies. However, while several mechanisms have been proposed, few have focused on regulation on intracellular Ca2+. In the present study, we further examined the effects of acute insulin on calcium pathways in primary hippocampal neurons in culture. Using the whole-cell patch-clamp technique, we found that acute insulin delivery reduced voltage-gated calcium currents. Fura-2 imaging was used to also address acute insulin effects on spontaneous and depolarization-mediated Ca2+ transients. Results indicate that insulin reduced Ca2+ transients, which appears to have involved a reduction in ryanodine receptor function. Together, these results suggest insulin regulates pathways that control intracellular Ca2+ which may reduce the AHP and improve memory. This may be one mechanism contributing to improved memory recall in response to intranasal insulin therapy in the clinic.

Effect of amlodipine on cytosolic calcium and apoptosis in hyperglycemia induced-human neuronal cell line culture

“…Hyperglycemia induced cell had higher levels of Ca 2+ than normoglycemia cell. This result similar to study by Verkhratsky, 2008, which revealed that chronic glucose exposure induced elevation of Ca 2+ intracellular of neuron [4,5]. Boldizsar et al, stated that hyperglicemia could increase cytosolic calcium level in human T cell [6].…”

Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents

“…Results show that while constitutive activity was obtained, VGCC current density was unaffected. This result is surprising, given the acute and robust effects of exogenous insulin on VGCC and ryanodine receptor function in hippocampal neurons previously reported by our lab [14]. Ongoing studies are investigating the ability of hippocampal neurons to maintain insulin signaling across time to better define mechanisms of insulin insensitivity in the brain, i.e.…”

“…Insulin signaling in the brain is an integral physiological component of proper neurological function and has been shown to help maintain receptor trafficking (AMPA, NMDA, GABA A ) [1–5], increase cerebral blood flow [6–10], stimulate glucose transporter translocation [11,12], reduce voltage-gated calcium channel (VGCC) function [13–15], reduce neuroinflammation [16], and reduce ryanodine receptor function [14]. Studies on age-related alterations in insulin signaling have highlighted a reduction in insulin receptor density and insulin receptor mRNA in aged brains [17–20].…”

Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages

“…Insulin has also been described to impact intracellular calcium homeostasis. A recent study by the Thibault lab reported that acute insulin administration decreases calcium transients ultimately affecting the function of intracellular calcium channels (Maimaiti et al, 2017 ). Understanding this relationship is necessary, as higher levels of intracellular calcium may consequently disrupt physiologic glucose metabolism in the brain; potentially promoting further pathology (Pancani et al, 2011 ).…”