International Journal of Research ISSN NO:2236-6124 A Review on Ion Channels and Gap Junctions: A Comparative Account on Normal Cell Proliferation and Cancer Progression Ayyagari Ramlal1 and Laxman Kumar2* 1Department of Botany, Affiliated to Hindu College, University of Delhi, India 2Department of Botany, Jamia Hamdard, New Delhi, India [email protected], [email protected] Abstract Ion channels are accountable for numerous extracellular and intracellular physiological processes where they contribute to maintaining ion homeostasis, signalling and potential of the membrane. Cancer, one amongst deadliest among all diseases, is outlined as a group of diseases caused by the unrestricted proliferation of normal cells that overlooks the natural laws of cell division. Ion channels have a pivotal role in cell proliferation. Involvement of ion channels in the progression of cancer has been revealed long back and deciphering the underlying principles involved in the ion channel-mediated cancer progression has been a major sphere in recent research. The cell interactions are essential to multicellular organisms for their development and required for the normal functioning of the body which includes tight and gap junctions. Gap junctions are intracellular channels allowing to and fro movements of ions across cells. This article emphasizes the potentialities of some voltage-gated ion channels (VGICs) including Chloride, Potassium and Sodium (VGKCs, VGSCs and CLCAs) and gap junctions which have been identified during cancer development and along with some therapeutic controls. The expression of these channels in some cases is directly concerned with the cancer development whereas some others show indirect participation. Ion channels have two roles in the promotion of abnormality within cells and regulation or forestalling of the signalling cascade. Cell-to-cell interactions provided by Gap junctions (GJs) could lead to cause serious complications like cancer once they go unregulated and altered. Keywords: Voltage-gated ion channels (VGICs), ion channels, cancer progression, gap junctions and therapeutic controls 1. Introduction Involvement of ion channels in normal cell division Ions have played significant roles in signalling pathways across the cell membrane and other membranes. Monovalent ions like Sodium and Potassium primarily play a job in the adjustment of membrane potential whereas the divalent ions like Magnesium, Zinc and Calcium are crucial for intracellular signalling processes and act as secondary messengers. [1] Fundamental processes like contraction of muscles, secretion, the synaptic transmission including generation *Corresponding author: [email protected] | +91 9911425929 Volume IX, Issue V, May/2020 Page No:1 International Journal of Research ISSN NO:2236-6124 and propagation of action potential is all mediated by ion channels. [3] Expression of various ion channels in cells during the adaptive and innate immunity and their opening control the influx-efflux of ions via the plasma membrane (PM) and endoplasmic reticulum or lysosomes or mitochondrion. [1] Cell division and cell proliferation is a very complex phenomenon is under the tight regulation of proteins, molecules and various ions. ATP, calcium ions, cyclin-dependent kinases (CDKs) and cyclins all are part of the cell cycle machinery. The chief component which maintains the cell cycle is its membrane potential. The electrical potential is generated by the ion transporters and channels which is created by the intra- and extracellular ion concentration. There was less or no mitoses in the cells like muscle and neuron which showed much-hyperpolarised resting potential. The excitable roles of ion channels include generation of action potentials and contraction in neurons and muscles respectively. Apart from these functions, voltage-gated channels also include in non-excitable roles like homeostasis maintenance via regulating ion transport and volume regulation. [2] Cells are continuously degraded and recycled by the process of autophagy, studies revealed that ion fluxes created across membranes have played a major role in the regulation of autophagy. This process supports other physiological processes as well like cell differentiation, embryonic development and immunity and its malfunction may cause cardiovascular, infections, metabolic diseases and cancer as well. [3] Cell cycle is under the tight regulation of voltage-gated potassium channels, experiments carried on unfertilised oocytes of mouse showed that activity remained high during the M and G1 phase, while it reduced during synthesis (S) and G2 phases. [19] Gap junctions represent the group of internal membrane proteins that direct the exchange of amino acids, small peptides, ions and sugars across the neighbouring cells. Connexins form the gap junctions in vertebrates while in invertebrates it is formed from innexins. Cx43, Cx40 and Cx45, the dominant isoforms of connexins-gap junctions show their expression in the heart and play a major role in carrying the currents between the myocardium cells. These GJs are unevenly distributed in the ventricle and atrial regions thereby resulting in anisotropy of heart tissues. [21] The transition from normal to abnormal cell proliferation Ion channels are made up of macromolecular proteins that span through the cell membrane via lipid bilayer and allows the passage of ions and are essential for cell proliferation along within the development of cancer as well [4, 5]. As a result of protein structural conformational changes, it causes the channel to open. Small changes happened in the structure allows the in and out the movement of ions up to 10 million ions/sec. It consists of an aqueous pore which is accessible to selective ions. Depending upon the opening agent, they can be broadly divided into voltage-gated and ligand-gated, the former one requires the potential difference across the membranes to open while the latter one requires a particular signal which can activate their channelling like neurotransmitters channels [4]. Cancer is marked by the abnormal growth and proliferation of cells which encompasses the alteration of genes and/or proteins which are required for fundamental processes of survival, proliferation, differentiation and cell death [7]. It is classified into many categories based on the site of production of an abnormal mass of cells. The channels and carriers which transport ions across the membranes have a vital role in the regulation of cell survival, death and mortality. The altered regulation of these channels may result in the transformation of normal cells into cancerous cells. Many studies show that alterations or modifications in the channels or gates may impact various cascades related to cancer growth like tumour cell survival and proliferation, malignant progression and invasive behaviour of normal cells. (Florian Lang, 2014) [6]. Calcium-mediated Volume IX, Issue V, May/2020 Page No:2 International Journal of Research ISSN NO:2236-6124 channels, K+ channels, Sodium and other anions channels have shown their roles in the enhancement of tumour and its metastasis. The present concern among the research community is that the natural process of cell death is not followed by the cancerous cells, therefore the resistance and insensitivity acquired by cancerous cells against apoptosis must be overcome. [13] The transmuted expression of a channel can be utilised for various diagnostic purposes; recent shreds of evidence show that blocking the activity of channels results in impediment of tumour growth. The transient receptor potential protein (TRPs) act as regulators of stimuli like temperature, vision, taste and other sensory responses via ion fluxes. A subfamily of TRPs called TRPM (TRP-Melastatin) which function in regulating the cationic fluxes such as K+, Ca2+, and Mg2+ etc. [15] Expression anomalies of connexions have known to cause diseases like cardiac hypertrophy and ischemia. Recent studies revealed that gap junctions implicated in Charcot-Marie-Tooth and visceroatrial heterotaxia syndrome (CMT and VHS) inherited diseases, [22] It was observed that increased expression levels of mRNA and protein were observed in some tumours along with mislocalization of connexins, for instance, prostate cancer has Cx43 and Cx32 and pancreatic and colon cancer showed Cx26 expression. [23] Cationic channels 1. Potassium channels Studies revealed that overexpression of calcium-activated K+ channel called BK channels one of the voltage-gated ion channels are entailed in the progression of cancer. Huge genetic diversity and channel properties within potassium channels can be seen (V. Suppiramaniam et al, 2017). These BK channels are found in a broad range of cells and are energised by the increasing levels of intracellular calcium and other molecules and mechanisms. [7] They are crucial for the release of neurotransmitters, muscle relaxation along with processes involved in tumorigenesis. In vitro studies revealed that glioma cell growth, survival and migration are strongly controlled by BK channels. Mansoor Abdul et al (2003) showed that potassium channels also participate in the proliferation of breast cancer. The T-lymphocytes are dependent on the voltage-gated K channels (VGPCs) for their activation, kv1.3 is an essential component which activates the peripheral T-cells. [8] the drugs like dequalinium and amiodarone are potent growth suppressors as they bind to the K-channels and inactivate them thus, control the proliferation