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Differential up-regulation of Na⁺-Ca²⁺ exchange by phosphoarginine and ATP in dialysed squid axons

Reinaldo DiPolo * and Luis Beaugé ¹

1. The aim of this study was to characterize further the two main metabolic pathways of regulation of the Na⁺-Ca²⁺ exchanger in squid axons induced by its two naturally ocurring high-energy compounds: ATP and phosphoarginine (Pa). [Na⁺]_o-dependent Ca²⁺ efflux (forward Na⁺_o-Ca²⁺_i exchange) and [Ca²⁺]_o-dependent Ca²⁺ efflux (Ca²⁺_o-Ca²⁺_i exchange) were measured in internally dialysed squid axons at 16-17 °C.

2. Measurements of changes in the apparent affinity of the Na⁺-Ca²⁺ exchanger for transporting (Na⁺_o, Na⁺_i, Ca²⁺_o, Ca²⁺_i) and regulatory (Ca²⁺_i) ions induced by ATP and Pa show marked differences for the two substrates: (i) ATP strongly alters the affinity for Na⁺_o and Na⁺_i, while Pa does not, and (ii) in the absence of Na⁺_i, ATP has no stimulatiory effect; on the other hand, Pa causes a dramatic increase in Na⁺_o-Ca²⁺_i exchange with little activation of Ca²⁺_o-Ca²⁺_i exchange.

3. The MgATP analogue chromium-ATP (CrATP) completely inhibits MgATP stimulation of the Na⁺-Ca²⁺ exchanger. Nevertheless, even with the effects of the nucleotide blocked, Pa exhibits its usual activation of the [Na⁺]_o-dependent Ca²⁺ efflux.

4. None of the classical serine-threonine-tyrosine kinase inhibitors, nor the PP₁ and PP₂ phosphatase inhibitors, affects either the ATP or the Pa effect. However, intracellular microinjections of an exogenous phosphatase (alkaline phosphatase) completely reverses the stimulation of the Na⁺-Ca²⁺ exchange induced by ATP and Pa.

5. Prolonged intracellular dialysis with highly permeable porous capillaries (18 kDa molecular weight cut-off), which normally induces a complete run-down of the MgATP effect, does not alter the Pa stimulation of the exchanger, even after 6 h of continuous dialysis.

6. We conclude that the ATP and Pa modulation of Na⁺-Ca²⁺ exchange in an invertebrate nerve fibre are two genuinely different mechanisms, which affect the carrier properties in very different ways. An interesting similarity between ATP and Pa is that a phosphorylation-dephosphorylation process seems to be a common feature of these two regulation modes.

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