Role and mechanisms of regulation of the basolateral Kir 4.1/Kir 5.1K+ channels in the distal tubules.

Epithelial K+ channels are essential for maintaining electrolyte and fluid homeostasis in the kidney. It is recognized that basolateral inward-rectifying K+ (Kir ) channels play an important role in the control of resting membrane potential and transepithelial voltage, thereby modulating water and electrolyte transport in the distal part of nephron and collecting duct. Monomeric Kir 4.1 (encoded by Kcnj10 gene) and heteromeric Kir 4.1/Kir 5.1 (Kir 4.1 together with Kir 5.1 (Kcnj16)) channels are abundantly expressed at the basolateral membranes of the distal convoluted tubule and the cortical collecting duct cells. Loss-of-function mutations in KCNJ10 cause EAST/SeSAME tubulopathy in humans associated with salt wasting, hypomagnesaemia, metabolic alkalosis and hypokalaemia. In contrast, mice lacking Kir 5.1 have severe renal phenotype that, apart from hypokalaemia, is the opposite of the phenotype seen in EAST/SeSAME syndrome. Experimental advances using genetic animal models provided critical insights into the physiological role of these channels in electrolyte homeostasis and the control of kidney function. Here, we discuss current knowledge about K+ channels at the basolateral membrane of the distal tubules with specific focus on the homomeric Kir 4.1 and heteromeric Kir 4.1/Kir 5.1 channels. Recently identified molecular mechanisms regulating expression and activity of these channels, such as cell acidification, dopamine, insulin and insulin-like growth factor-1, Src family protein tyrosine kinases, as well as the role of these channels in NCC-mediated transport in the distal convoluted tubules, are also described.

ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex.

Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca(2+)-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca(2+)-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity.