Ion transporters do not function in isolation from each other. In fact, the activity of a transporter is modulated by the other components of the transport machinery so that the cellular volume, ion concentration and electrochemical gradients are preserved. For example, in shark rectal gland cells an increase in Cl^- entry trough channels triggers Cl^- extrusion trough a Na⁺:K⁺:2Cl^- cotransporter, thus intracellular Cl^- remains constant. The importance of these cross-talk mechanisms is highlighted by the pathological consequences that emerge when disrupted. In cystic fibrosis patients epithelial Na⁺ channels (ENaC) are hyperactive due to the loss of cross-talk with the Cl^- channel CFTR that is mutated. Resulting in the alteration of the direction of fluid transport causing the airway surface epithelia to reabsorb fluid, instead of secrete, thus collapsing the cilia and impeding mucociliary clearance. Another example is Liddle’s syndrome, a rare genetic form of hypertension where ENaC is mutated and fails to respond to regulatory mechanism such as Na⁺-dependant feedback inhibition (i.e., inhibition of ENaC by intracellular Na⁺). Resulting in increased sodium reabsorption by the distal nephron, expanded plasma volume and elevated blood pressure. However, in spite of the importance of the cross-talk mechanisms in the pathobiology of these and other diseases we have an incomplete and poor understanding of the molecular mechanisms involved.

Several physiological strategies have been reported to be involved in cross-talk in vertebrate cells. Intracellular calcium has been implicated in the cross-talk in mammalian salivary glands and frog kidney. However, despite many advances in the field we still do not have a clear and comprehensive understanding of the mechanisms of cross-talk between ion transport systems. The insect Malpighian tubule cells are an ideal model to study the molecular and cellular basis of cross-talk mechanisms during transport.