TY - JOUR T1 - Dopamine requires unique residues to signal via the serotonin 2A receptor. JF - Neuroscience Y1 - 2020 A1 - Soman, Shuchita A1 - Bhattacharya, Aditi A1 - Panicker, Mitradas M AB -

Serotonin is an important neurotransmitter and neuromodulator. Disruption of the serotonergic system has been implicated in various psychiatric disorders such as schizophrenia and bipolar disorder. Most of the drugs targeting these neurotransmitter systems are classified primarily as agonists or inverse agonists/antagonists, with their described function being limited to activating the canonical signaling pathway(s), or inhibiting the pathway(s) respectively. Previous work with the human 5-HT has shown the receptor to be activated by dopamine, also an endogenous ligand. Dopamine is the cognate ligand of the dopaminergic system, which significantly overlaps with the serotonergic system in the brain. The two systems innervate many of the same brain areas, and the central serotonergic systems also regulate dopamine functions. Our aim was to investigate the downstream signaling set up by the receptor on being activated by dopamine. We show that dopamine is a functionally selective ligand at 5-HT and have examined dopamine as a ligand with respect to some receptor-dependent phenotypes. Our results show that dopamine acts as an agonist at the human serotonin 2A receptor and brings about its activation and internalization. Using in vitro assays, we have established differences in the signaling pathways set up by dopamine as compared to serotonin. Using site-specific mutagenesis we have identified residues important for this functional selectivity, shown by dopamine at this receptor. Our identification of specific residues important in the functional selectivity of dopamine at 5-HT could have far reaching implications for the field of GPCR signaling and drug-design. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

VL - 439 ER - TY - JOUR T1 - Derivation of iPSC lines from two patients with familial Alzheimer's disease from India. JF - Stem Cell Res Y1 - 2019 A1 - Najar, Ashaq H A1 - Sneha, K M A1 - Ashok, Aparna A1 - Babu, Swathy A1 - Subramaniam, Anand G A1 - Kannan, Ramkrishnan A1 - Viswanath, Biju A1 - Purushottam, Meera A1 - Varghese, Mathew A1 - Parvez, Suhel A1 - Panicker, Mitradas M A1 - Mukherjee, Odity A1 - Jain, Sanjeev AB -

The current prevalence of diagnosable dementia in India is 1% of people over 60 years (~3.7 million people), but is estimated to increase significantly, as ~15% world's aged population (>65 years) would be resident here by 2020 (Shah et al., 2016). While several mutations that pose a familial risk have been identified, the ethnic background may influence disease susceptibility, clinical presentation and treatment response. In this study, we report a detailed characterization of two representative HiPSC lines from a well-characterized dementia cohort from India. Availability of these lines, and associated molecular and clinical information, would be useful in the detailed exploration of the genomic contribution(s) to AD.

VL - 34 ER - TY - JOUR T1 - Serotonin is essential for eye regeneration in planaria Schmidtea mediterranea. JF - FEBS Lett Y1 - 2019 A1 - Sarkar, Arunabha A1 - Mukundan, Namita A1 - Sowndarya, Sai A1 - Dubey, Vinay Kumar A1 - Babu, Rosana A1 - Lakshmanan, Vairavan A1 - Rangiah, Kannan A1 - Panicker, Mitradas M A1 - Palakodeti, Dasaradhi A1 - Subramanian, Sabarinath Peruvemba A1 - Ramaswamy, Subramanian AB -

Planaria is an ideal system to study factors involved in regeneration and tissue homeostasis. Little is known about the role of metabolites and small molecules in stem cell maintenance and lineage specification in planarians. Using liquid chromatography and mass spectrometry (LC-MS)-based quantitative metabolomics, we determined the relative levels of metabolites in stem cells, progenitors, and differentiated cells of the planarian Schmidtea mediterranea. Tryptophan and its metabolic product serotonin are significantly enriched in stem cells and progenitor population. Serotonin biosynthesis in these cells is brought about by a non-canonical enzyme, phenylalanine hydroxylase (PAH). Knockdown of Smed-pah leads to complete disappearance of eyes in regenerating planaria, while exogenous supply of serotonin and its precursor rescue the eyeless phenotype. Our results demonstrate a key role for serotonin in eye regeneration.

ER - TY - JOUR T1 - Discovery biology of neuropsychiatric syndromes (DBNS): a center for integrating clinical medicine and basic science. JF - BMC Psychiatry Y1 - 2018 A1 - Viswanath, Biju A1 - Rao, Naren P A1 - Narayanaswamy, Janardhanan C A1 - Sivakumar, Palanimuthu T A1 - Kandasamy, Arun A1 - Kesavan, Muralidharan A1 - Mehta, Urvakhsh Meherwan A1 - Venkatasubramanian, Ganesan A1 - John, John P A1 - Mukherjee, Odity A1 - Purushottam, Meera A1 - Kannan, Ramakrishnan A1 - Mehta, Bhupesh A1 - Kandavel, Thennarasu A1 - Binukumar, B A1 - Saini, Jitender A1 - Jayarajan, Deepak A1 - Shyamsundar, A A1 - Moirangthem, Sydney A1 - Vijay Kumar, K G A1 - Thirthalli, Jagadisha A1 - Chandra, Prabha S A1 - Gangadhar, Bangalore N A1 - Murthy, Pratima A1 - Panicker, Mitradas M A1 - Bhalla, Upinder S A1 - Chattarji, Sumantra A1 - Benegal, Vivek A1 - Varghese, Mathew A1 - Reddy, Janardhan Y C A1 - Raghu, Padinjat A1 - Rao, Mahendra A1 - Jain, Sanjeev AB -

BACKGROUND: There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes (schizophrenia, bipolar disorder, obsessive compulsive disorder, Alzheimer's dementia and substance use disorders), identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository.

METHODS: The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing.

DISCUSSION: We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area.

VL - 18 IS - 1 ER - TY - JOUR T1 - Mutation burden profile in familial Alzheimer's disease cases from India. JF - Neurobiol Aging Y1 - 2018 A1 - Syama, Adhikarla A1 - Sen, Somdatta A1 - Kota, Lakshmi Narayanan A1 - Viswanath, Biju A1 - Purushottam, Meera A1 - Varghese, Mathew A1 - Jain, Sanjeev A1 - Panicker, Mitradas M A1 - Mukherjee, Odity KW - Aged KW - Alzheimer Disease KW - Amyloid beta-Protein Precursor KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - India KW - LDL-Receptor Related Proteins KW - Membrane Transport Proteins KW - Middle Aged KW - Mutation KW - Presenilin-1 KW - Risk KW - Signal Transduction KW - Tissue Plasminogen Activator KW - Whole Exome Sequencing AB -

This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

VL - 64 ER -