Projects and Publications

LRRC8B in calcium signaling

Intracellular calcium stored within the endoplasmic reticulum (ER) plays a critical role in controlling many cellular events, such as ER-stress, secretion, protein folding, apoptosis, etc. Perturbation of ER calcium homeostasis may lead to several diseases like neurodegenerative diseases, diabetes and cancer. ER calcium level is maintained by the interplay of several transporters, channels and calcium-binding proteins. ER-resident protein SERCA (sarco- endoplasmic-reticulum calcium-ATPase) actively pumps calcium into the ER, whereas IP3 receptors remove calcium from ER upon its activation by IP3. Calcium from the ER goes out passively by a ‘leak channel’. The identity and properties of ‘leak channel’ are not very clear, though several proteins like presenilin and Bcl-2 have been implicated in the process of calcium leak from ER. Recently we showed that LRRC8B (Leucine-rich repeat-containing 8) protein is a major player of cellular calcium signaling and a legitimate leak channel. We are studying the involvement of LRRC8B in calcium homeostasis in detail.

Pannexin in health and disease

Pannexins are the channel forming proteins, ubiquitously expressed in many cell types including glial cells and neuron. Pannexins have been implicated in many physiological as well as pathophysiological processes. Hyperactivation of pannexins have been linked to neuroinflammation and neurodegeneration. In glial cells, pannexin-1 works as a major gliotransmitter release channel during inflammation. ATP, released through panneanxin-1 channel triggers varieties of signaling cascades both in paracrine and autocrine fashion. ATP acts on P2X and P2Y receptors leading to increase of intracellular calcium which is followed by the activation of different signaling pathways. It has been shown that pannexin-1 couples with P2X7 receptor and they work in concert regulating different cellular events. During neuroinflammation, ATP released through pannexin-1 channel activates P2X7 receptor causing excessive rise of intracellular calcium and thereby promotes cell death. We are studying the role of Pannexin-1/P2X7 in Parkinson’s disease and ischemia.

Acid-sensing ion channels in stroke

In India, more than a million people suffer strokes each year. During ischemic stroke, insufficient oxygen supply to the brain tissue is followed by a drop in extracellular pH that in turn activates calcium-permeable ‘Acid-Sensing Ion Channels’ (ASICs). The excessive rise in intracellular calcium is believed to be one of the causes of neuronal death. Although the crystal structure of ASIC has been published recently, the mechanism of ASIC-opening/closing (gating) is not clear. We are studying the conformational changes that occur during channel gating from the closed to open/desensitized states. We are also trying to find out small molecules for treating stroke by blocking ASICs.

Selected Publications

Friesacher T, Reddy HP, Bernsteiner H; Combista JC, Shalomov B, Bera AK, Zangerl-Plessl EM; Dascal N; Stary-Weinzinge A (2022) A selectivity filter mutation provides insights into gating regulation of a K+ channel. Communications Biology DOI 10.1038/s42003-022-03303-1

Shalomov B, Handklo-Jamal R, Reddy HP, Theodor N, , Dascal N (2022) A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5). J Physiol. 600, 1419-1437.

Reddy HP, Yakubovich D, Keren-Raifman T, Tabak G, Tsemakhovich VA, Pedersen MH, Shalomov B, Colombo S, Goldstein DB, Javitch JA, Bera AK, Dascal N (2021) Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels. iScience. 24(9):103018.

Purohit R, Bera AK (2021) Pannexin 1 plays a pro-survival role by attenuating P2X7 receptor-mediated Ca2+ influx. Cell calcium. 99, 102458

Ghosh A, Khandelwal N, Kumar A, Bera AK (2017) Leucine-rich repeat-containing 8B (LRRC8B) protein is associated with the endoplasmic reticulum calcium leak in HEK293 cells: J Cell Sci 130 (22):3818-3828.

Tewari D, Majumdar D, Vallabhaneni S, Bera AK (2017) Aspirin induces cell death by directly modulating mitochondrial voltage-dependent anion channel (VDAC). Sci Rep 7, 45184; doi: 10.1038/srep45184.

K R, Savant S, Giri H, Ghosh A, Fisslthaler B, Fleming I, Ram U, Bera AK, Augustin HG, Dixit M (2016) Angiopoietin-2 mediates thrombin-induced monocyte adhesion and endothelial permeability. J Thromb Haemost. 14(8):1655-1667.

Poornima V, Vallabhaneni S, Mukhopadhyay M, Bera AK (2015) Nitric oxide inhibits the pannexin 1 channel through a cGMP-PKG dependent pathway. Nitric Oxide 47: 77-84.

Singh PK, Ghosh D, Tewari D, Mohite GM Carvalho E; Jha NN, Jacob RS, Sahay S, Banerjee R, Bera AK, Maji SK (2015) Cytotoxic Helix-Rich Oligomer formation by Melittin and Pancreatic Polypeptide. PLOS ONE 10(3):e0120346.

Priya MK, Sahu G, Pantoja DRS, Goldy N, Meenakshi A, Jadhav V, Saran U, Ali BMJ, Roberts DD, Bera AK, Chatterjee S (2015) Tipping off endothelial tubes: Nitric oxide drives tip cells. Angeogenesis 18(2):175-189.

Tewari D, Ahmed T, Chirasani VR, Singh PK, Maji SK, Senapati S , Bera AK (2015) Modulation of the Mitochondrial Voltage Dependent Anion Channel (VDAC) by Curcumin. Biochim Biophys Acta 1848(1 Pt A):151-158.

Saha T, Dasari S, Tewari D, Prathap A, Sureshan KM, Bera AK, Mukherjee A, Talukdar P (2014) Hopping Mediated Anion Transport through a Mannitol-Based Rosette Ion Channel. J Am Chem Soc 136(40):14128-35

Sahu G, Sukumaran S, Bera AK (2014) Pannexins form gap junctions with electrophysiological and pharmacological properties distinct from connexins. Sci Rep 4:4955.

Allu PKR, Chirasani VR, Ghosh D, Mani A, Bera AK, et al. (2014) Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation. J Biol Chem 289 (7):4455-4469.

Sahu G and Bera AK (2013) Contribution of intracellular calcium and pH in ischemic uncoupling of cardiac gap junction channels formed of connexins 43, 40, and 45: a critical function of C-terminal domain. PLOS ONE 8(3):e60506.

Sahu BS, Obbineni JM, Sahu G, Allu PKR, Subramanian L, Sonawane PJ, Singh PK, Sasi BK, Senapati S, Maji SK, Bera AK, et al. (2012) Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population. J Biol Chem 287(52):43840-43852.

Sahu BS, Obbineni JM, Sahu G, Singh P, Sonawane P, Sasi B, Allu PKR, Maji S, Bera AK, et al.(2012) Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor. J Cell Sci 125, 2323-2337.

Jetti SK, Swain SM, Majumder S, Chatterjee S, Poornima V and Bera AK (2010) Evaluation of the role of nitric oxide in acid sensing ion channel mediated cell death. Nitric Oxide 22, 213-21.

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