Investigating Adrenoceptor Regulation of the Astroglial Glycogen Reserve
thesisposted on 02.08.2017, 14:26 by Xianguo Jiang
There is increasing evidence that astrocytes can play crucial roles in signalling within the central nervous system. In particular, astrocytes can communicate with each other and also with neurons, the latter interaction giving rise to the concept of the “tripartite synapse”. Thus, as well as astrocytes playing a homeostatic role to maintain an optimal extracellular environment within the brain, this cell-type may play roles in an array of CNS processes, including neurotransmission and synaptic activity. Astrocytes appear to be unique within the CNS in that they can store glucose in the form of glycogen. This constitutes the only energy reserve of the brain, and has been shown to play an important role not only at times of metabolic crisis, but also in supporting normal physiological brain function, including higher functions, such as learning and memory. Primary rat cerebral cortex (and cerebellar) astrocytes have been studied to advance our understanding of how cell-surface receptors control glycogen turnover, focusing on the roles played by the key neurotransmitter, noradrenaline. Evidence is presented for the presence of multiple adrenoceptor subtypes in astrocytes, including β1-, α1- and α2-adrenoceptors. β1-adrenoceptor activation resulted in robust accumulation of adenosine 3’,5’-cyclic-monophosphate (cAMP), with ≤5% of the maximal cAMP response elicited by noradrenaline being sufficient to activate near-maximally glycogenolysis. The observed cAMP response to noradrenaline in astrocytes is the sum of stimulatory β1-adrenoceptor-, and inhibitory α2-adrenoceptor-mediated effects. Because of the amplification of signal observed between cAMP and glycogenolysis, the inhibitory α2-adrenoceptor-mediated effect is only observed at the level of the glycogenolytic response over a small concentration range that may nevertheless coincide with the physiological range for noradrenaline effects on astrocytic function. Interestingly, α2-adrenoceptor activation also appears to increase the rate of glycogen re-synthesis and to have a “glycogen-loading” effect on astrocytes, increasing resting glycogen concentrations in cells. In contrast, while noradrenaline also stimulated a robust increase in intracellular Ca2+ concentration ([Ca2+]i), no evidence was found of this α1-adrenoceptor-mediated effect being able to contribute to the glycogenolytic response. Thus, while the sarco/endoplasmic reticular Ca2+-ATPase inhibitor, thapsigargin, and membrane depolarization (by increasing [K+]o) could each evoke increases in [Ca2+]i and stimulate glycogenolyis, addition of α1-adrenoceptor-selective agonists did not. These data increase our understanding of how the neurotransmitter, noradrenaline exerts its actions in astrocytes to regulate glycogenolysis, as well as a variety of other signal transduction pathways.