Chandan Goswami

Publications of Chandan Goswami

• Conservation of Tubulin-Binding Sequences in TRPV1 throughout Evolution.

  Authors: Puspendu Sardar, Abhishek Kumar, Anita Bhandari, Chandan Goswami

  PloS one. 01/2012; 7(4):e31448.

  Transient Receptor Potential Vanilloid sub type 1 (TRPV1), commonly known as capsaicin receptor can detect multiple stimuli ranging from noxious compounds, low pH, temperature as well asTransient Receptor Potential Vanilloid sub type 1 (TRPV1), commonly known as capsaicin receptor can detect multiple stimuli ranging from noxious compounds, low pH, temperature as well as electromagnetic wave at different ranges. In addition, this receptor is involved in multiple physiological and sensory processes. Therefore, functions of TRPV1 have direct influences on adaptation and further evolution also. Availability of various eukaryotic genomic sequences in public domain facilitates us in studying the molecular evolution of TRPV1 protein and the respective conservation of certain domains, motifs and interacting regions that are functionally important. Using statistical and bioinformatics tools, our analysis reveals that TRPV1 has evolved about ∼420 million years ago (MYA). Our analysis reveals that specific regions, domains and motifs of TRPV1 has gone through different selection pressure and thus have different levels of conservation. We found that among all, TRP box is the most conserved and thus have functional significance. Our results also indicate that the tubulin binding sequences (TBS) have evolutionary significance as these stretch sequences are more conserved than many other essential regions of TRPV1. The overall distribution of positively charged residues within the TBS motifs is conserved throughout evolution. In silico analysis reveals that the TBS-1 and TBS-2 of TRPV1 can form helical structures and may play important role in TRPV1 function. Our analysis identifies the regions of TRPV1, which are important for structure - function relationship. This analysis indicates that tubulin binding sequence-1 (TBS-1) near the TRP-box forms a potential helix and the tubulin interactions with TRPV1 via TBS-1 have evolutionary significance. This interaction may be required for the proper channel function and regulation and may also have significance in the context of Taxol®-induced neuropathy.

• Right time - right location - right move: TRPs find motors for common functions.

  Authors: Rakesh Majhi, Puspendu Sardar, Luna Goswami, Chandan Goswami

  Channels (Austin, Tex.). 07/2011; 5(4):375-81.

  TRP channels are localized at specialized sub-cellular compartments like filopodial tips, ciliary structures, growth cones and spines that have importance in the context of several sensory functions.TRP channels are localized at specialized sub-cellular compartments like filopodial tips, ciliary structures, growth cones and spines that have importance in the context of several sensory functions. Several motor proteins largely regulate these localizations. Recent studies indicate that both physical and genetic interactions exist between TRP channels with actin and microtubule-based motor proteins. These two groups of proteins share specialized and fine regulation underlying physiological functions. Indeed, mutations causing loss of these interactions and regulations result in development of pathophysiological disorders and syndromes. In this review we analyze the recent progress made in cell-biological, biochemical, electrophysiological and genetic studies and summarize the multi-dimensional crosstalk between TRP channels with different motor proteins.

• Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway.

  Authors: Chandan Goswami, Julia Kuhn, Olayinka A Dina, Gregorio Fernández-Ballester, Jon D Levine, Antonio Ferrer-Montiel, Tim Hucho

  Journal of neurochemistry. 06/2011; 117(6):995-1008.

  Recently, we described estrogen and agonists of the G-protein coupled estrogen receptor GPR30 to induce protein kinase C (PKC)ε-dependent pain sensitization. PKCε phosphorylates the ion channelRecently, we described estrogen and agonists of the G-protein coupled estrogen receptor GPR30 to induce protein kinase C (PKC)ε-dependent pain sensitization. PKCε phosphorylates the ion channel transient receptor potential, vanilloid subclass I (TRPV1) close to a novel microtubule-TRPV1 binding site. We now modeled the binding of tubulin to the TRPV1 C-terminus. The model suggests PKCε phosphorylation of TRPV1-S800 to abolish the tubulin-TRPV1 interaction. Indeed, in vitro PKCε phosphorylation of TRPV1 hindered tubulin-binding to TRPV1. In vivo, treatment of sensory neurons and F-11 cells with estrogen and the GPR30 agonist, G-1, resulted in microtubule destabilization and retraction of microtubules from filopodial structures. We found estrogen and G-1 to regulate the stability of the microtubular network via PKC phosphorylation of the PKCε-phosphorylation site TRPV1-S800. Microtubule disassembly was not, however, dependent on TRPV1 ion conductivity. TRPV1 knock-down in rats inverted the effect of the microtubule-modulating drugs, Taxol and Nocodazole, on estrogen-induced and PKCε-dependent mechanical pain sensitization. Thus, we suggest the C-terminus of TRPV1 to be a signaling intermediate downstream of estrogen and PKCε, regulating microtubule-stability and microtubule-dependent pain sensitization.

• Structural and functional regulation of growth cone, filopodia and synaptic sites by TRPV1.

  Authors: Chandan Goswami

  Communicative & integrative biology. 11/2010; 3(6):614-8.

  Specialized neuronal structures namely growth cones, filopodia and spines are important entities by which neurons communicate with each other, integrate multiple signaling events, consolidateSpecialized neuronal structures namely growth cones, filopodia and spines are important entities by which neurons communicate with each other, integrate multiple signaling events, consolidate interacting structures and exchange synaptic information. Recent studies confirmed that Transient Receptor Potential Vanilloid sub type 1 (TRPV1), alternatively known as capsaicin receptor, forms a signaling complex at the plasma membrane and integrate multiple exogenous and endogenous signaling cues there. This receptor localizes in the neuronal growth cones and also in filopodial tips. In addition, TRPV1 is endogenously present in synaptic structures and located both in pre- and post-synaptic spines of cortical neurons. Being nonselective Ca(2+)-channel, TRPV1 regulates the morphology and the functions of these structures by various mechanisms. Our studies indicated that physical interaction with signaling and structural molecules, modulation of different cytoskeleton, synaptic scaffolding structures and vesicle recycling by Ca(2+)-dependent and -independent events are the key mechanisms by which TRPV1 regulates growth cone, filopodia and spines in a coordinated manner. TRPV1 not only regulates the morphology, but also regulates the functions of these entities. Thus TRPV1 is important not only for the detection of noxious stimuli and transmission of pain signaling, but also are for the neuronal communications and network formation.

• Filamentous microtubules in the neuronal spinous process and the role of microtubule regulatory drugs in neuropathic pain.

  Authors: Chandan Goswami, Luna Goswami

  Neurochemistry international. 11/2010; 57(5):497-503.

  Structural and regulatory components in the spinous processes neurons are still not fully understood. While the presence, regulation and function of actin cytoskeleton are now well established,Structural and regulatory components in the spinous processes neurons are still not fully understood. While the presence, regulation and function of actin cytoskeleton are now well established, involvement of microtubule cytoskeleton is only now being studied. In spite of biochemical, genetic and anatomical evidence, neurobiologists have experienced difficulties to even establish the physical presence and to demonstrate the functional relevance of "filamentous microtubules" in the spines. However, recent studies have demonstrated that filamentous microtubules regularly invade most spines. Moreover, functional aspects like stabilization and maturation of spines can be directly correlated with the presence of these microtubules; low doses of microtubule stabilizers can induce as many as 50% more spines. Clinically, knowledge of microtubule active drugs is extremely important, especially in the area of oncology, where they are commonly used as anti-neoplastic agents. Unfortunately, a major dose-limiting side effect of this class of drugs is a painful peripheral neuropathy. We review the recent concept of microtubules in the spine, and also critically analyze their role in chemotherapy-induced neuropathic pain.

• TRPV1 acts as a synaptic protein and regulates vesicle recycling.

  Authors: Chandan Goswami, Nils Rademacher, Karl-Heinz Smalla, Vera Kalscheuer, Hans-Hilger Ropers, Eckart D Gundelfinger, Tim Hucho

  Journal of cell science. 06/2010; 123(Pt 12):2045-57.

  Electrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as theElectrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as the central nervous system, the questions remain whether TRPV1 is present in synaptic structures and whether it is involved in synaptic processes. In the present study we gathered evidence that TRPV1 can be detected in spines of cortical neurons, that it colocalizes with both pre- and postsynaptic proteins, and that it regulates spine morphology. Moreover, TRPV1 is also present in biochemically prepared synaptosomes endogenously. In F11 cells, a cell line derived from dorsal-root-ganglion neurons, TRPV1 is enriched in the tips of elongated filopodia and also at sites of cell-cell contact. In addition, we also detected TRPV1 in synaptic transport vesicles, and in transport packets within filopodia and neurites. Using FM4-64 dye, we demonstrate that recycling and/or fusion of these vesicles can be rapidly modulated by TRPV1 activation, leading to rapid reorganization of filopodial structure. These data suggest that TRPV1 is involved in processes such as neuronal network formation, synapse modulation and release of synaptic transmitters.

• Importance of non-selective cation channel TRPV4 interaction with cytoskeleton and their reciprocal regulations in cultured cells.

  Authors: Chandan Goswami, Julia Kuhn, Paul A Heppenstall, Tim Hucho

  PloS one. 01/2010; 5(7):e11654.

  TRPV4 and the cellular cytoskeleton have each been reported to influence cellular mechanosensitive processes as well as the development of mechanical hyperalgesia. If and how TRPV4 interacts with theTRPV4 and the cellular cytoskeleton have each been reported to influence cellular mechanosensitive processes as well as the development of mechanical hyperalgesia. If and how TRPV4 interacts with the microtubule and actin cytoskeleton at a molecular and functional level is not known. We investigated the interaction of TRPV4 with cytoskeletal components biochemically, cell biologically by observing morphological changes of DRG-neurons and DRG-neuron-derived F-11 cells, as well as functionally with calcium imaging. We find that TRPV4 physically interacts with tubulin, actin and neurofilament proteins as well as the nociceptive molecules PKCepsilon and CamKII. The C-terminus of TRPV4 is sufficient for the direct interaction with tubulin and actin, both with their soluble and their polymeric forms. Actin and tubulin compete for binding. The interaction with TRPV4 stabilizes microtubules even under depolymerizing conditions in vitro. Accordingly, in cellular systems TRPV4 colocalizes with actin and microtubules enriched structures at submembranous regions. Both expression and activation of TRPV4 induces striking morphological changes affecting lamellipodial, filopodial, growth cone, and neurite structures in non-neuronal cells, in DRG-neuron derived F11 cells, and also in IB4-positive DRG neurons. The functional interaction of TRPV4 and the cytoskeleton is mutual as Taxol, a microtubule stabilizer, reduces the Ca2+-influx via TRPV4. TRPV4 acts as a regulator for both, the microtubule and the actin. In turn, we describe that microtubule dynamics are an important regulator of TRPV4 activity. TRPV4 forms a supra-molecular complex containing cytoskeletal proteins and regulatory kinases. Thereby it can integrate signaling of various intracellular second messengers and signaling cascades, as well as cytoskeletal dynamics. This study points out the existence of cross-talks between non-selective cation channels and cytoskeleton at multiple levels. These cross talks may help us to understand the molecular basis of the Taxol-induced neuropathic pain development commonly observed in cancer patients.

• Submembraneous microtubule cytoskeleton: biochemical and functional interplay of TRP channels with the cytoskeleton.

  Authors: Chandan Goswami, Tim Hucho

  The FEBS journal. 09/2008;

  Much work has focused on the electrophysiological properties of transient receptor potential channels. Recently, a novel aspect of importance emerged: the interplay of transient receptor potentialMuch work has focused on the electrophysiological properties of transient receptor potential channels. Recently, a novel aspect of importance emerged: the interplay of transient receptor potential channels with the cytoskeleton. Recent data suggest a direct interaction and functional repercussion for both binding partners. The bi-directionality of physical and functional interaction renders therefore, the cytoskeleton a potent integration point of complex biological signalling events, from both the cytoplasm and the extracellular space. In this minireview, we focus mostly on the interaction of the cytoskeleton with transient receptor potential vanilloid channels. Thereby, we point out the functional importance of cytoskeleton components both as modulator and as modulated downstream effector. The resulting implications for patho-biological situations are discussed.

• Novel aspects of the submembraneous microtubule cytoskeleton.

  Authors: Chandan Goswami, Tim Hucho

  The FEBS journal. 09/2008;

• GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat.

  Authors: Julia Kuhn, Olayinka A Dina, Chandan Goswami, Vanessa Suckow, Jon D Levine, Tim Hucho

  The European journal of neuroscience. 05/2008; 27(7):1700-9.

  We evaluated the signalling pathway by which estrogen acts in peripheral tissue to produce protein kinase Cepsilon (PKCepsilon)-dependent mechanical hyperalgesia. Specific agonists for the classicalWe evaluated the signalling pathway by which estrogen acts in peripheral tissue to produce protein kinase Cepsilon (PKCepsilon)-dependent mechanical hyperalgesia. Specific agonists for the classical estrogen receptors (ER), ERalpha and ERbeta, did not result in activation of PKCepsilon in neurons of dissociated rat dorsal root ganglia. In contrast, G-1, a specific agonist of the recently identified G-protein-coupled estrogen receptor, GPR30, induced PKCepsilon translocation. Involvement of GPR30 and independence of ERalpha and ERbeta was confirmed using the GPR30 agonist and simultaneous ERalpha and ERbeta antagonist ICI 182,780 (fulvestrant). The GPR30 transcript could be amplified from dorsal root ganglia tissue. We found estrogen-induced as well as GPR30-agonist-induced PKCepsilon translocation to be restricted to the subgroup of nociceptive neurons positive for isolectin IB4 from Bandeiraea simplicifolia. Corroborating the cellular results, both GPR30 agonists, G-1 as well as ICI 182,780, resulted in the onset of PKCepsilon-dependent mechanical hyperalgesia if injected into paws of adult rats. We therefore suggest that estrogen acts acutely at GPR30 in nociceptors to produce mechanical hyperalgesia.

• A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation.

  Authors: Mohammad Mahdi Motazacker, Benjamin Rainer Rost, Tim Hucho, Masoud Garshasbi, Kimia Kahrizi, Reinhard Ullmann, Seyedeh Sedigheh Abedini, Sahar Esmaeeli Nieh, Saeid Hosseini Amini, Chandan Goswami, Andreas Tzschach, Lars Riff Jensen, Dietmar Schmitz, Hans-Hilger Ropers, Hossein Najmabadi, Andreas Walter Kuss

  American journal of human genetics. 11/2007; 81(4):792-8.

  Nonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, theyNonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, they are still largely unexplored. Here, we report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family. The predicted gene product lacks the first ligand-binding domain, the adjacent transmembrane domain, and the putative pore loop, suggesting a complete loss of function of the GLU(K6) protein, which is supported by electrophysiological data. This finding provides the first proof that GLU(K6) is indispensable for higher brain functions in humans, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation.

• TRPV1 acts as a synaptic protein and regulates vesicle recycling.

  Authors: Chandan Goswami, Nils Rademacher, Karl-Heinz Smalla, Vera M Kalscheuer, Hans-Hilger Ropers, Eckart D Gundelfinger, Tim Hucho

  Journal of Cell Science, v.123, 2045-2057 (2010).

  Electrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as theElectrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as the central nervous system, the questions remain whether TRPV1 is present in synaptic structures and whether it is involved in synaptic processes. In the present study we gathered evidence that TRPV1 can be detected in spines of cortical neurons, that it colocalizes with both pre- and postsynaptic proteins, and that it regulates spine morphology. Moreover, TRPV1 is also present in biochemically prepared synaptosomes endogenously. In F11 cells, a cell line derived from dorsal-root-ganglion neurons, TRPV1 is enriched in the tips of elongated filopodia and also at sites of cell-cell contact. In addition, we also detected TRPV1 in synaptic transport vesicles, and in transport packets within filopodia and neurites. Using FM4-64 dye, we demonstrate that recycling and/or fusion of these vesicles can be rapidly modulated by TRPV1 activation, leading to rapid reorganization of filopodial structure. These data suggest that TRPV1 is involved in processes such as neuronal network formation, synapse modulation and release of synaptic transmitters.

• Transient Receptor Potential channels: What's happening? Reflections in the wake of the 2009 TRP Meeting, Karolinska Institutet, Stockholm.

  Authors: Chandan Goswami, Md Shahidul Islam

  Channels (Austin, Tex.). 4(2):124-35.

  More than 150 participants from 25 countries gathered in Stockholm during 25(th) to 27(th) Sept 2009 to attend the meeting "TRP channels: from sensory signaling to human disease" and enjoyed anMore than 150 participants from 25 countries gathered in Stockholm during 25(th) to 27(th) Sept 2009 to attend the meeting "TRP channels: from sensory signaling to human disease" and enjoyed an international, intensive and vibrant meeting. This meeting shed lights on the recent advances made in this field of research in different sectors of biology, and identified directions for future research and the areas where TRP channels could be used as potential targets for prevention and treatment of human diseases. The participants of this meeting shared their recent largely unpublished data, state-of-the-art techniques and their critical views which would push research in this field forward in the new decade. Another major outcome of this meeting was the realization that extensive work remains to be done to develop the necessary tools and enhance the quality of research in this area so that the prevailing controversies can be resolved. In this report we summarize the latest scientific excitements, some critical issues, as well as some future directions for research that were addressed and discussed in this meeting.

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• TRPV4-mediated channelopathies.

  Authors: Pratibha Verma, Ashutosh Kumar, Chandan Goswami

  Channels (Austin, Tex.). 4(4):319-28.

  Transient receptor potential vanilloid sub type 4 (TRPV4) is a member of non-selective cation channel that is important for sensation of several physical and chemical stimuli and also involved inTransient receptor potential vanilloid sub type 4 (TRPV4) is a member of non-selective cation channel that is important for sensation of several physical and chemical stimuli and also involved in multiple physiological functions. Recently it gained immense medical and clinical interest as several independent studies have demonstrated that mutations in the TRPV4 gene can results in genetic disorders like Brachyolmia, Charcot-Marie-Tooth disease type 2C, Spinal Muscular Atrophy and Hereditary Motor and Sensory Neuropathy type 2. Close analysis of the data obtained from these naturally occurring as well as other TRPV4 mutants suggest that it is not the altered channel activity of these mutants per se, but the involvement and interaction of other factors that seem to modulate oligomerization, trafficking and degradation of TRPV4 channels. Also, these factors can either enhance or reduce the activity of TRPV4. In addition, there are some potential signaling events that can also be involved in these genetic disorders. In this review, we analyzed how and what extent certain cellular and molecular functions like oligomerization, surface expression, ubiquitination and functional interactions might be affected by these mutations.