Potassium in Solid Cancers

Electrolyte disorders are a frequent finding in cancer patients. In the majority of cases the etiologies of such disorders are common to all cancer types (i.e. diuretic-induced hyponatremia or hypokalemia). Sometimes, electrolyte disorders are caused by paraneoplastic syndromes or are due to cancer therapy. Potassium is one of the most important electrolytes of the human body since it is involved in the regulation of muscle contraction, maintenance of the integrity of the skeleton, blood pressure and nerve transmission as well as in the normal function of cells. Potassium homeostasis is strictly regulated since the gap between the recommended daily dietary intake (120 mEq/day) and the levels stored in the extracellular fluid (around 70 mEq) is huge. Alterations of potassium homeostasis are frequent in cancer patients as well alterations in potassium channels, the transmembrane proteins that mediate potassium fluxes within the cells. The present chapter is focused on the clinical significance of potassium homeostasis and potassium channels in patients with solid tumors.

Potassium Homeostasis

The average potassium intake in the United States population ranges from 90 to 120 mEq/day. About 98% of the total body\'s potassium is intracellular, and only 2% is present in the extracellular compartment. This distributional proportion is essential for cellular metabolic reactions and maintaining a gradient for resting membrane potential. A loss of this gradient results in hyper- or hypopolarization of the cell membrane, especially in cardiac muscles leading to life-threatening arrhythmias. Multiple mechanisms in human maintain homeostasis. Transient initial changes are due to transcellular shifts activating sodium-potassium ATPase pumps on the cell membrane. The kidneys essentially take part in excess potassium excretion, maintaining total body stores constant within normal range. Gastrointestinal secretion of potassium is insignificant in individuals with normal renal function, however plays an essential role in individuals with compromised renal function. So far, a classic feedback mechanism was thought to maintain potassium homeostasis; however, a recently recognized feedforward mechanism acting independently also helps preserve potassium homeostasis. Hence, potassium homeostasis is vital for humans to function at a normal level.

With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron

Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K+ channel (BK)-dependent K+ secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca2+-permeable TRPV4 channel is essential for BK activation in the ASDN. Furthermore, high K+ diet increases TRPV4 activity and expression largely in an aldosterone-dependent manner. In the current study, we aimed to test whether WNK kinases contribute to regulation of TRPV4 activity and its stimulation by aldosterone. Systemic inhibition of WNK with WNK463 (1 mg/kgBW for 3 days) markedly decreased TRPV4-dependent Ca2+ influx in freshly isolated split-opened collecting ducts. Aldosterone greatly increased TRPV4 activity and expression in cultured mpkCCDc14 cells and this effect was abolished in the presence of WNK463. Selective inhibition of WNK1 with WNK-in-11 (400 nM, 24 h) recapitulated the effects of WNK463 on TRPV4-dependent Ca2+ influx. Interestingly, WNK-in-11 did not interfere with up-regulation of TRPV4 expression by aldosterone, but prevented translocation of the channel to the apical plasma membrane. Furthermore, co-expression of TRPV4 and WNK1 into Chinese hamster ovary (CHO) cells increased the macroscopic TRPV4-dependent cation currents. In contrast, over-expression of TRPV4 with a dominant negative WNK1 variant (K233M) decreased the whole-cell currents, suggesting both stimulatory and permissive roles of WNK1 in regulation of TRPV4 activity. Overall, we show that WNK1 is essential for setting functional TRPV4 expression in the ASDN at the baseline and in response to aldosterone. We propose that this new mechanism contributes to regulation of K+ secretion and, by extension, urinary K+ levels to maintain systemic potassium homeostasis.

Essentiality of c-di-AMP in Bacillus subtilis: Bypassing mutations converge in potassium and glutamate homeostasis

In order to adjust to changing environmental conditions, bacteria use nucleotide second messengers to transduce external signals and translate them into a specific cellular response. Cyclic di-adenosine monophosphate (c-di-AMP) is the only known essential nucleotide second messenger. In addition to the well-established role of this second messenger in the control of potassium homeostasis, we observed that glutamate is as toxic as potassium for a c-di-AMP-free strain of the Gram-positive model bacterium Bacillus subtilis. In this work, we isolated suppressor mutants that allow growth of a c-di-AMP-free strain under these toxic conditions. Characterization of glutamate resistant suppressors revealed that they contain pairs of mutations, in most cases affecting glutamate and potassium homeostasis. Among these mutations, several independent mutations affected a novel glutamate transporter, AimA (Amino acid importer A, formerly YbeC). This protein is the major transporter for glutamate and serine in B. subtilis. Unexpectedly, some of the isolated suppressor mutants could suppress glutamate toxicity by a combination of mutations that affect phospholipid biosynthesis and a specific gain-of-function mutation of a mechanosensitive channel of small conductance (YfkC) resulting in the acquisition of a device for glutamate export. Cultivation of the c-di-AMP-free strain on complex medium was an even greater challenge because the amounts of potassium, glutamate, and other osmolytes are substantially higher than in minimal medium. Suppressor mutants viable on complex medium could only be isolated under anaerobic conditions if one of the two c-di-AMP receptor proteins, DarA or DarB, was absent. Also on complex medium, potassium and osmolyte toxicity are the major bottlenecks for the growth of B. subtilis in the absence of c-di-AMP. Our results indicate that the essentiality of c-di-AMP in B. subtilis is caused by the global impact of the second messenger nucleotide on different aspects of cellular physiology.