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The last residue of the Na, K‐ATPase catalytic subunit isoform specific region (ISR) plays a critical role in Na, K‐ATPase membrane trafficking

The Isoform Specific Region (ISR) is a region of structural heterogeneity among the 4 isoforms of the Na, K‐ATPase α‐subunit. Replacing α1 ISR (K489NPNASEPKHL499) by α2 ISR sequence (E487REDSPQS‐HV496) results in a doubled response to PKC, suggesting that the ISR participates in isoform‐specific PKC regulation. PKC regulation of α1 involves membrane recycling via clathrin‐coated vesicles. In α1, L499 is immediately followed by another L, making it a potential di‐Leucine (LL) target motif for clathrin adaptor proteins. Replacing α1 ISR by α2 ISR disrupts this LL motif. To test whether this explains the change in PKC regulation observed when tampering with ISR, we compared a L499V mutant of α1 to the full length α1 in a model of heterologous expression of rat constructs in opossum kidney cells. In the absence of PKC stimulation, total expression and Na, K‐ATPase mediated 86Rb+ uptake were comparable in α1L499V and α1 expressing cells. However, biotinylation experiments revealed a higher surface expression of the mutant, suggesting that the mutation affected the steady state level of surface expression of the protein. Upon PKC stimulation, activation of Na, K‐ATPase mediated 86Rb+ uptake was doubled in mutant‐expressing cells. This suggests that the last residue of the ISR plays a critical role in Na,K‐ATPase isoform‐specific response to PKC activation and in steady‐state Na,K‐ATPase expression at the cell surface.