Developmental downregulation of ATP-sensitive potassium conductance in astrocytes in situ

Abstract

In many neural and non‐neural cells, ATP‐sensitive potassium (KATP) channels couple the membrane potential to energy metabolism. We investigated the activation of KATP currents in astrocytes of different brain regions (hippocampus, cerebellum, dorsal vagal nucleus) by recording whole‐cell currents with the patch‐clamp technique in acute rat brain slices. Pharmacological tools, hypoglycemia and specific compounds in the pipette solution (cAMP, UDP), were used to modulate putative KATP currents. The highest rate of KATP specific currents was observed with a pipette solution containing cAMP and external stimulation with diazoxide (0.3 mM). The diazoxide‐activated current had a reversal potential negative to −80 mV and was inhibited by tolbutamide (0.2 mM). We found that not all cells activated a KATP current, and that the portion of cells with functional KATP channel expression was developmentally downregulated. Whereas diazoxide activated KATP currents in 57% of the astrocytes in rats aged 8–11 days (n = 21), the rate decreased to 38% at 12–15 days (n = 29) and to 8% at 16–19 days (n = 12). No significant difference was observed for the three brain regions. In recordings without cAMP in the internal solution, only 21% (12–15 days; n = 19) or none (16–19 days; n = 7), respectively, showed a potassium current upon diazoxide application. This metabolically regulated potassium conductance may be of importance, particularly in immature astrocytes with a complex current pattern, which have a relatively high input resistance: KATP currents activated by energy depletion may hyperpolarize the cells, or stabilize a negative resting potential during depolarizing stimuli mediated, e.g., by glutamate receptors and/or uptake carriers. GLIA 32:205–213, 2000. © 2000 Wiley‐Liss, Inc.

Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions

“…The reasons for these discrepancies are unclear, but they may indicate heterogeneity of glial Kir6.0 channel expression, similar to that found for Kir2.0 and Kir4.1 channel subtypes (see above), and electrophysiological studies have shown heterogeneity in the expression of functional K ATP channels in astrocytes in the dorsal vagal nucleus, cerebellum and hippocampus [71,75,76]. Due to the ATP-sensitivity of Kir6.0, they are only active when intracellular concentrations of ATP fall to very low levels and therefore serve to maintain the high K + conductance and hyperpolarized RMP in glia during metabolic challenge [68,69,76]. Furthermore, immunoreactivity for astroglial Kir6.1 in the cerebellum is localized to astrocyte processes surrounding synapses, and mirrors that of neuronal Kir6.2, suggesting glial and neuronal K ATP channels may act in synergy during metabolic challenges in the brain [74].…”

“…However, in other studies, no expression of Kir6.2 mRNA was found in astrocytes or oligodendrocytes [73], and immunoreactivity for only Kir6.1 and not Kir6.2 subunits was found in hippocampal, cortical and cerebellar astrocytes and cerebellar Bergmann glia [74]. The reasons for these discrepancies are unclear, but they may indicate heterogeneity of glial Kir6.0 channel expression, similar to that found for Kir2.0 and Kir4.1 channel subtypes (see above), and electrophysiological studies have shown heterogeneity in the expression of functional K ATP channels in astrocytes in the dorsal vagal nucleus, cerebellum and hippocampus [71,75,76]. Due to the ATP-sensitivity of Kir6.0, they are only active when intracellular concentrations of ATP fall to very low levels and therefore serve to maintain the high K + conductance and hyperpolarized RMP in glia during metabolic challenge [68,69,76].…”

Adenosine and ATP-sensitive potassium channels modulate dopamine release in the anoxic turtle (Trachemys scripta) striatum

“…As Purkinje cells of the isolated turtle cerebellum also do not hyperpolarize during anoxia (43), the mechanism by which K ATP channels modulate DA homeostasis is not likely to be via cellular hyperpolarization; however, an alternative method is yet unknown. Research has suggested that K ATP channels may be modulated by a variety of signaling pathways, including neurotransmitter release, H 2 O 2 , and cAMP levels (3,7); it is quite possible then that K ATP channels, in turn, can act through second messenger systems directly, without cellular hyperpolarization. The turtle may provide an interesting model to investigate such mechanisms, as in the mammal, the opening of K ATP channels is invariably associated with hyperpolarization, and the possibility of more direct effects has not been examined.…”

Opening of Astrocytic Mitochondrial ATP-Sensitive Potassium Channels Upregulates Electrical Coupling between Hippocampal Astrocytes in Rat Brain Slices

“…Moreover, in the nervous system, K ATP channel activation is involved in the control of neuronal excitability [16]–[18] and seizure propagation [14], [19]–[24]. Given the importance of astrocytes on brain function [25] and the enrichment of K ATP channel in glial cells, K ATP channels might be responsible for some critical activities of astrocytes or at least play a role in them [26]–[28]. More recently, it has been revealed that activation of astrocytic K ATP channels, particularly the mitochondrial K ATP (mitoK ATP ) channels, affects glutamate uptake and astrocytic activation [29]–[32].…”