Figure 14.

Summary of the regulation of BLM K_ATP channel activity. (A) A simplified model of transcellular transport in the proximal tubule is shown. Driven by the electrochemical gradient, Na⁺ enters the cell across the apical membrane in exchange for protons or together with low molecular substrates like amino acids or glucose. Cl⁻ is taken up across the apical membrane by Cl⁻-base exchange and leaves the cell across the BLM through a CFTR-like Cl⁻ channel. Na⁺ is pumped out of the cell across the BLM by means of the Na⁺,K⁺,ATPase pump, which breaks down ATP and brings K⁺ ions into the cell. For steady state transport to continue, K⁺ has to recycle across the BLM. Recycling is mediated by basolateral K_ATP channels, which is activated by PKA and by the fall in [ATP]_i induced by the action of the pump when transport is stimulated. The BLM K_ATP channel is inhibited by decreased pH_i, increased [Ca²⁺]_i, PKC, and increases in [ATP]_i when transport is inhibited. This model links apical uptake of Na⁺ to cellular metabolism (ATP), which in turn is linked to the basolateral K⁺ conductance. (B) The dual effect of ATP: in the presence of Mg²⁺, a low concentration (100–200 μM) of ATP (or another hydrolyzable nucleotide triphosphate) is required to maintain K_ATP channel activity by acting at a high affinity nucleotide hydrolysis site (NHS). However, millimolar levels of ATP_i (or another NTP, NDP, or NMP) inhibit the channel, presumably by binding to a low affinity nucleotide binding domain (NBD). Nucleotide hydrolysis does not appear to be necessary for the inhibitory action of nucleotides at the NBD. K channel openers such as diazoxide may act by interfering with nucleotide binding to the NBD.