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Yogesh Kumar

Bio: Yogesh Kumar is an academic researcher from University of California, Los Angeles. The author has contributed to research in topics: Plasmin & Aprotinin. The author has an hindex of 6, co-authored 11 publications receiving 436 citations.

Papers
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Journal ArticleDOI
TL;DR: It is speculated that the molecular multiplicity of the C‐terminus (and intracellular loops) dictated by alternative exons may modulate or create additional interacting sites in a tissue‐specific manner.
Abstract: The basic functional unit of the large-conductance, voltage- and Ca2+-activated K+ (MaxiK, BK, BKCa) channel is a tetramer of the pore-forming α-subunit (MaxiKα) encoded by a single gene, Slo, holding multiple alternative exons. Depending on the tissue, MaxiKα can associate with modulatory β-subunits (β1–β4) increasing its functional diversity. As MaxiK senses and regulates membrane voltage and intracellular Ca2+, it links cell excitability with cell signalling and metabolism. Thus, MaxiK is a key regulator of vital body functions, like blood flow, uresis, immunity and neurotransmission. Epilepsy with paroxysmal dyskinesia syndrome has been recognized as a MaxiKα-related disorder caused by a gain-of-function C-terminus mutation. This channel region is also emerging as a key recognition module containing sequences for MaxiKα interaction with its surrounding signalling partners, and its targeting to cell-specific microdomains. The growing list of interacting proteins highlights the possibility that associations with the C-terminus of MaxiKα are dynamic and depending on each cellular environment. We speculate that the molecular multiplicity of the C-terminus (and intracellular loops) dictated by alternative exons may modulate or create additional interacting sites in a tissue-specific manner. A challenge is the dissection of MaxiK macromolecular signalling complexes in different tissues and their temporal association/dissociation according to the stimulus.

236 citations

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TL;DR: The results suggest 1007YNMLCFGIY1015 possible participation in Slo1 plasmalemmal targeting and demonstrate its role as a main mechanism for caveolin-1 association withSlo1 potentially serving a dual role: (i) maintaining channels in intracellular compartments downsizing their surface expression and/or (ii) serving as anchor of plasma membrane resident channels to caveolin -1-rich membranes.

73 citations

Journal ArticleDOI
TL;DR: KD1-L17R was equally or more effective than aprotinin or tranexamic acid, which have been used as antifibrinolytic agents to prevent blood loss during major surgery/trauma and in a mouse liver laceration bleeding model.

42 citations

Journal ArticleDOI
TL;DR: Results highlight c‐Src activation as one of the early and pivotal mechanisms in 5‐HT2AR contractile signalling in aorta as well as supporting a role of c-Src upstream of Rho kinase.
Abstract: Serotonin (5-hydroxytryptamine, 5-HT) receptors (5-HTRs) play critical roles in brain and cardiovascular functions In the vasculature, 5-HT induces potent vasoconstrictions, which in aorta are mainly mediated by activation of the 5-HT2AR subtype We previously proposed that one signalling mechanism of 5-HT-induced vasoconstriction could be c-Src, a member of the Src tyrosine kinase family We now provide evidence for a central role of c-Src in 5-HT2AR-mediated contraction Inhibition of Src kinase activity with 10 μm 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) prior to contraction resulted in ∼90–99% inhibition of contractions induced by 5-HT or by α-methyl-5-HT (5-HT2R agonist) In contrast, PP2 pretreatment only partly inhibited contractions induced by angiotensin II and the thromboxane A2 mimetic, U46619, and had no significant action on phenylephrine-induced contractions 5-Hydroxytryptamine increased Src kinase activity and PP2-sensitive tyrosine-phosphorylated proteins As expected for c-Src identity, PP2 pretreatment inhibited 5-HT-induced contraction with an IC50 of ∼1 μm Ketanserin (10 nm), a 5-HT2A antagonist, but not antagonists of 5-HT2BR (100 nm SB204741) or 5-HT2CR (20 nm RS102221), prevented 5-HT-induced contractions, mimicking PP2 and implicating 5-HT2AR as the major receptor subtype coupled to c-Src In HEK 293T cells, c-Src and 5-HT2AR were reciprocally co-immunoprecipitated and co-localized at the cell periphery Finally, 5-HT-induced Src activity was unaffected by inhibition of Rho kinase, supporting a role of c-Src upstream of Rho kinase Together, the results highlight c-Src activation as one of the early and pivotal mechanisms in 5-HT2AR contractile signalling in aorta

42 citations

Journal ArticleDOI
TL;DR: TFPI-2 in platelets from normal or pregnant subjects and in plasma from pregnant women binds FV/Va and regulates intrinsic coagulation and fibrinolysis and promotes clot stabilization while attenuating intrinsic clotting.

20 citations


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Journal ArticleDOI
11 Nov 2010-Nature
TL;DR: It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles.
Abstract: Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.

2,062 citations

Journal Article
TL;DR: The role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer are described and advances in the understanding ofPAR-1-mediated intracellular signaling and receptor desensitization are identified.

922 citations

Journal ArticleDOI
TL;DR: Present knowledge on the physiological role of ancillary KV channel subunits and their effects on Kv channel properties are critically reviewed.
Abstract: Since the first discovery of Kvβ-subunits more than 15 years ago, many more ancillary Kv channel subunits were characterized, for example, KChIPs, KCNEs, and BKβ-subunits. The ancillary subunits are often integral parts of native Kv channels, which, therefore, are mostly multiprotein complexes composed of voltage-sensing and pore-forming Kvα-subunits and of ancillary or β-subunits. Apparently, Kv channels need the ancillary subunits to fulfill their many different cell physiological roles. This is reflected by the large structural diversity observed with ancillary subunit structures. They range from proteins with transmembrane segments and extracellular domains to purely cytoplasmic proteins. Ancillary subunits modulate Kv channel gating but can also have a great impact on channel assembly, on channel trafficking to and from the cellular surface, and on targeting Kv channels to different cellular compartments. The importance of the role of accessory subunits is further emphasized by the number of mutations that are associated in both humans and animals with diseases like hypertension, epilepsy, arrhythmogenesis, periodic paralysis, and hypothyroidism. Interestingly, several ancillary subunits have in vitro enzymatic activity; for example, Kvβ-subunits are oxidoreductases, or modulate enzymatic activity, i.e., KChIP3 modulates presenilin activity. Thus different modes of β-subunit association and of functional impact on Kv channels can be delineated, making it difficult to extract common principles underlying Kvα- and β-subunit interactions. We critically review present knowledge on the physiological role of ancillary Kv channel subunits and their effects on Kv channel properties.

257 citations

Journal ArticleDOI
TL;DR: Recent insights into protein complexes associated with K(Ca) channels as revealed by proteomic research are summarized and the results available on structure and function of these complexes and on the underlying protein-protein interactions are discussed.
Abstract: Molecular research on ion channels has demonstrated that many of these integral membrane proteins associate with partner proteins, often versatile in their function, or even assemble into stable ma...

240 citations

Journal ArticleDOI
TL;DR: A review of the existing evidence for raft modulation of channel function can be found in this article, where the authors highlight some of the important evidence for the role of membrane rafts in channel function.
Abstract: Many types of ion channel localize to cholesterol and sphingolipid-enriched regions of the plasma membrane known as lipid microdomains or ‘rafts’. The precise physiological role of these unique lipid microenvironments remains elusive due largely to difficulties associated with studying these potentially extremely small and dynamic domains. Nevertheless, increasing evidence suggests that membrane rafts regulate channel function in a number of different ways. Raft-enriched lipids such as cholesterol and sphingolipids exert effects on channel activity either through direct protein–lipid interactions or by influencing the physical properties of the bilayer. Rafts also appear to selectively recruit interacting signalling molecules to generate subcellular compartments that may be important for efficient and selective signal transduction. Direct interaction with raft-associated scaffold proteins such as caveolin can also influence channel function by altering gating kinetics or by affecting trafficking and surface expression. Selective association of ion channels with specific lipid microenvironments within the membrane is thus likely to be an important and fundamental regulatory aspect of channel physiology. This brief review highlights some of the existing evidence for raft modulation of channel function.

229 citations