Intracellular K～+ Selectively Regulates The DNA Binding Activities Of Transcription Factors To Control Neuronal Survival

Apoptosis plays crucial roles in the normal tissue homeostasis. The molecularmechanism of apoptosis has been extensively investigated. More and more evidenceshowed that K~+ homeostasis plays an important role in apoptosis. Excessive K~+efflux and intracellular K~+ loss is a common event in apoptosis of many cell types.Recent studies demonstrated that decrease of intracellular K~+ concentration ([K~+]i) is akey step in early stage of apoptosis and low [K~+]i may serve as a death signal allowingthe execution of the suicide program. Blocking K~+ loss by K~+ channel blocker orelevating extracellular [K~+] prevents apoptosis. However, the mechanism how low[K~+]i promotes apoptosis remains unclear. Since many transcription factors have beenreported involved in neuron apoptosis, gene transcription plays important roles inapoptosis. We hypothesized that low [K~+]i might regulate the expression ofapoptotic genes through direct and selective effect on DNA binding activities of sometranscription factors to promote apoptosis.Using EMSAs we found that low [K~+] promotes DNA binding activities ofNF-κB, p53, Forkheand, HIF and Oct-1, whereas inhibited that of CREB, AP-1 andNPAS2. DNA binding activities of SP1, STAT, E2F, YY1, C/EBP and Egr-1 werenot affected by different [K~+]. Interestingly, NF-κB, p53, Forkheand and HIF arereported as proapoptotic transcription factors whereas CREB and AP1 promote cellsurvival. Using rat cortical neurons deprived of serum or treated by K~+ ionophoresas models for K~+ loss-induced apoptosis, we provide evidence that decreased [K~+]iincreased the expression of Bcl-XS, BAX and Bim, the downstream pro-apoptoticgenes of NF-κB, p53 and Forkhead respectively whereas decreased that of c-fos,Nur77 and Nor-1, the downstream genes of CREB. ChIP assays demonstrated thatin vivo NF-κB/DNA binding activity increased when [K+]i decreased in neurons. Allthese results supported the notion that [K+]i might directly and selectively affect DNAbinding of various transcription factors and regulate the expression of theirdownstream genes to promote neuronal apoptosis.