**2. Diverse role of** *KCNMA1* **in glioma**

**1. Introduction**

228 Brain Tumors - An Update

**1.1.** *KCNMA1***-encoded BKCa channels in glioma**

pared to BKCa channels in healthy glial cells [9, 10].

calcium bowl) segments.

Brain tumors are the most common type of solid tumors. In the United States, an estimated 20,000 new primary brain tumor cases are reported [1]. The most common form of malignant glioma is glioblastoma multiforme (GBM). The treatment of brain tumors is highly complicated due to their highly aggressive phenotypic and genotypic changes [2]. The median survival among GBM patients is only 15 months or less [3]. GBM contains heterogeneous subpopulations of glioma and other mixed supporting cells that are cancerous cells. They have the intrinsic ability that adapt in the brain tumor microenvironment and invade the normal brain. Gene expression profiling studies have identified many genes that have distinct expression patterns among different histological types and grades of gliomas [4]. The response of "normal cells" to malignant transformation involves changes in gene expression and is thought to be regulated by transcription [5]. The potassium ion channels are implicated in the malignant transformation to a higher grade in several cancers [5–7]. For example, we reported that low-

grade gliomas might undergo certain epigenetic changes to develop into a GBM [8].

The physiological features of BKCa channels also known as maxi K or BK channels are well described [6–9]. These channels are unique since its activity is triggered by depolarization and enhanced by an increase in μM range of cytosolic calcium (**Figure 1**). The BKCa channels provide a crucial link between the metabolic and electrical states of cells. The BKCa channel overexpression was observed in biopsies of patients with malignant gliomas compared with nonmalignant human cortical tissues and the level of expression correlated positively with increased malignancy [7]. Studies have shown the importance of BKCa channels in brain tumor biology [5]. Lastly, BKCa currents in glioma cells are more sensitive to intracellular [Ca2+] com-

**Figure 1.** BKCa channel is a tetramer of four monomeric pore-forming alpha-subunits encoded by *KCNMA1*. The seven transmembrane channels S0 to S6 are voltage-sensing domains, S1 to S4 channels form pore domain, S5 is a selectivity filter, and S6 is a extracellular N-terminal segment. The cytoplasmic C-terminal domain has RCK1 and RCK2 (with *KCNMA1***-encoded** BKCa channel plays a pivotal role in cancer cell proliferation. Amplification of *KCNMA1* was observed in breast, ovarian, and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3–7%) and gliomas. *KCNMA1* amplification was significantly associated with high tumor stage, highgrade, high tumor cell proliferation, and poor prognosis. Due to the large number of protein interactions and activating factors influencing BKCa channel function, intracellular Ca2+, membrane voltage, pH, shear stress, carbon monoxide, phosphorylation states, and steroid hormones, it is generally difficult to predict its direct role in a given tissue. However, in many diseases including cancers, defective regulation and/or expression of BKCa channels have repeatedly been associated with altered cell cycle progression [11], cell proliferation [11], and cell migration [11]. These altered cell functions are implicated in development of malignancy [11].
