Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection

• Published in: PloS one 2015-04, Vol.10 (4), p.e0124263-e0124263
• Main Authors: Antony, Cecil, Mehto, Subhash, Tiwari, Brijendra K, Singh, Yogendra, Natarajan, Krishnamurthy
• Format: Article
• Language: English
• Subjects: Ambedkar, Bhimrao Ramji (1891-1956); Animals; Antigen presenting cells; Antigens; Apoptosis; Biomedical research; Calcium; Calcium - metabolism; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium Channels - genetics; Calcium Channels - metabolism; Calcium homeostasis; Cell Adhesion Molecules - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cytokines; Dendritic cells; Disease Models, Animal; Female; Flow Cytometry; Gene Expression; Genomics; Health aspects; Homeostasis; Immunology; Infections; Infectious diseases; Lymphocytes; Macrophages; Macrophages - immunology; Macrophages - metabolism; Membrane Proteins - metabolism; Mice; Models, Biological; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Neoplasm Proteins - metabolism; Oxygen; Pathogenesis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiratory Burst - genetics; Second messengers; Signal Transduction; siRNA; STIM1 protein; Stromal Interaction Molecule 1; Stromal Interaction Molecule 2; Transcription factors; Transcription Factors - metabolism; Tuberculosis; Tuberculosis - genetics; Tuberculosis - immunology; Tuberculosis - metabolism; Tuberculosis - microbiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124263

We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection.