– or glycolyticderived power might rely on whether NKA is activated on the extracellular K+-binding web site or the intracellular Na+-binding internet site, respectively.Relative importance of AMP, HCO3-/cAMP/PKA/PhK and Ca2+/PhK routes in K+-induced glycogenolysisSince glycogen phosphorylase in brain astrocytes is regulated through both phosphorylation by PhK and allosteric activation by AMP, understanding the relative value of those mechanisms really should be provided priority. For example, closer look in the effect of excessNeurochem Int. Author manuscript; offered in PMC 2014 November 01.DiNuzzo et al.Pageextracellular K+ on cAMP (Figure 2 in Choi et al., 2012) suggests that much less than 20 improve in cAMP level at 10 mM K+ will be far from what normally is necessary to stimulate glycogenolysis. Moreover, quantitative evaluation of NBC function and its dependence on NKA-established gradients in comparison to K+ uptake indicated that the price of NBC activity usually is at least many times reduce than NKA/NKCC activity in astrocytes (see discussion in Peng et al., 2012). Eventually, Ca2+-activated PhK received the strongest help because the main target enzyme for regulation of GP (see `Possible recurrent signaling between NKA, glycogen and Ca2+ signaling’ section). This would determine the mixed phosphorylation/allosteric activation route by elevated Ca2+ concentration because the major element in the course of K+-stimulated glycogenolysis, as outlined by a comparable effect acting in muscle (Ozawa, 2011). Nonetheless, as allosteric handle is quicker than enzyme phosphorylation cascades, GPb could be critical inside the first seconds of enhanced energy demand prior to covalent modification for the enzyme takes spot (Walcott and Lehman, 2007). The very higher sensitivity to AMP exhibited by brain GPa and GPb is clearly evidenced by their higher AMP binding affinity (low Km), which is substantially greater compared with muscle isoforms (Guenard et al., 1977; Lowry et al., 1967). On the other hand, the low affinity (high Km) of brain GPa and GPb for glycogen implies poor enzyme activity at low AMP concentration no matter phosphorylation states (see discussion in Crerar et al., 1995). The phosphorylation state of muscle GP has as an alternative a big influence on enzyme activation (Lowry et al., 1967). In quantitative terms, the relative contribution of phosphorylation versus allosteric control of glycogen phosphorylase remains to be elucidated. It must be kept in mind, nonetheless, that the activation of PKA by cAMP also stimulates the conversion of cAMP to AMP by soluble phosphodiesterase (PDE) IV, which exhibits higher affinity for cAMP and is activated in response to phosphorylation by PKA (Madelian and La Vigne, 1996).Rucaparib This means that allosteric and phosphorylation activation mechanisms are inter-related.Cefepime Activation of PhK was also reported to become mediated by autophosphorylation-dependent protein kinase inside a cAMP- and Ca2+-independent pathway (Yu and Yang, 1995).PMID:23910527 Ultimately, the spatiotemporal dependence of K+-induced glycogenolysis needs to be taken into account when figuring out modifications in GP activity developed by a distinct pathway. Nevertheless, this detailed characterization is experimentally challenging, and adds towards the limitations represented by tissue or cell culture preparations.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptConcluding remarksThe notion that glycogen in astrocytes is necessary for sequestration of excess extracellular K+ after neuronal activity (Xu et al.