What is Cell Biology?What is cell signalingWhy do we study Cell BiologyClassification of the cells?Comparative analysis of the different cells

Significant Events in Cell Biology There have been several significant events throughout history that have led to the development of the field of cell biology as it exists today. Below are a few of these major events:1655 - Robert Hooke gives first description of a cork tree cell. 1674 - Leeuwenhoek views protozoa. 1683 - Leeuwenhoek views bacteria. 1831 - Robert Brown was first to identify thenucleusas an important cell component. 1838 - Schleiden and Schwann introduce what would become the Cell Theory. 1857 - Kolliker describesmitochondria. 1869 - Miescher isolates DNA for the first time. 1882 - Kock identifies bacteria. 1898 - Golgi discovers theGolgi apparatus. 1931 - Ruska builds the first Transmission Electron Microscope. 1953 - Watson and Crick propose structure of DNAdouble-helix. 1965 - First commercial Scanning Electron Microscope produced. 1997 - First sheepcloned. 1998 - Mice cloned. 2003 - Human genome DNA sequence draft completed.http://biology.about.com/od/cellbiology/a/cellbiology.htm

1.Cellular Signaling: General principles of signaling by cell surface receptors, endocrine, paracrine and autocrine signaling, types of cellular responses induced by signaling molecules, components of intracellular signal-transudation pathways.

2. Short Term Signaling: G-protein coupled receptor system, General mechanism of the activation of effectors molecules associated with G-protein-coupled receptors, G-protein coupled receptors that activate or inhibit adenylate cyclase, G-protein coupled receptors that activate phospholipase C, and G-protein coupled receptors that regulate ion channels.

Cell Biology-IILS-1&2

Sense, amplify and response (genetic, biochemical, physiological)

Autocrine, paracrine, endocrine and intracrine (Steriods)

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common process in human cancers.

Dynamic, short term and long term cellular responses

Signaling molecule: DNA, RNA, Protein, Small molecules, gaseous molecule, Photon, mechanical forces etc

Input (receptor), processor (transducer) and output (effectors)

A prototypical neuropeptide receptor is depicted that couples tothe indicated signaling pathways through Gq and G12,13 proteins.Signal pathways regulated by neuropeptide receptors.

Interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.Oncogene (2001) 20, 1563 -1569

Autocrine or paracrine signals also activate intrinsic growth-factor receptor tyrosine kinases, and cytokine-receptor associated Janus-family kinases (JAKs) and SRC family tyrosine kinases, which, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3).

In transformed cells, STAT3 can also be activated by constitutively active non-receptor tyrosine kinases such as SRC and ABL.

After tyrosine phosphorylation, STAT3 molecules dimerize and translocate to the nucleus, where they directly regulate gene expression.

STAT3 signaling is normally tightly regulated by several inhibitory molecules, including suppressor of cytokine signalling (SOCS) proteins, protein inhibitor of activated STAT (PIAS) proteins and protein tyrosine phosphatases (PTPases).

In cancer cells, however, overactive receptor and non-receptor tyrosine kinases cause persistent STAT3 phosphorylation and activation.NATURE REVIEWS | IMMUNOLOGYVOLUME 7 | JANUARY 2007

Constitutive activation of STAT3 by receptor and non-receptor tyrosine kinases.

Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation Cells release adenosine triphosphate (ATP), which activates plasma membranelocalized P2X and P2Y receptors and thereby modulates cellular function in an autocrine or paracrine manner.

Release of ATP and the subsequent activation of P2 receptors establish the basal level of activation (sometimes termed "the set point") for signal transduction pathways and regulate a wide array of responses that include tissue blood flow, ion transport, cell volume regulation, neuronal signaling, and host-pathogen interactions.

Basal release and autocrine or paracrine responses to ATP are multifunctional, evolutionarilyconserved, and provide an economical means for the modulation of cell, tissue, and organismal biology. R. Corriden, P. A. Insel, Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation. Sci. Signal. 3, re1 (2010).

Prototype GPCR

Seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors.

Establish communication between environment and cellular side.

Integral membrane proteins.

The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins.

G protein-coupled receptors are involved in many diseases, and are also the target of around half of all modern medicinal drugs.

GPCR signaling route-(a) Cyclase (b) Phosphatidylinositol-DAG-Kinase and PIP3-Receptors

GPCR+Ligand-Conformational changes-GEF-activation of G protein-Galpha-Effector-Outcome

Desensitization

Cycling of receptors

Class A (or 1) (Rhodopsin-like)-Subdivision for 19 group Class B (or 2) (Secretin receptor family)

Class C (or 3) (Metabotropic glutamate/pheromone) Class D (or 4) (Fungal mating pheromone receptors)

Class E (or 5) (Cyclic AMP receptors)

Class F (or 6) (Frizzled/Smoothened) Classification of GPCR

Functional ImportanceImmunity

Vision

Smell

Psychological

Aging-Population

Common structural component are responsible for wide physiological diversity.

Epinephrine-Glucose to Glucose-1-phosphate-Energy Metabolism

Epinephrine--adrenergic receptors (Heart, Smooth Muscles arteries) Rise in cAMP

Prototype of GPCR and G-proteins Cycle

A Heterotrimeric G Protein Gilman and Rodbell-Activation of enzyme indirectlyNP in 1994Signaling molecule-Activation (Conformational change leads to GEF activity)-GTPTermination- Hydrolysis of GTP with the help of GAP proteins

Conformational Changes in G On Nucleotide Exchange

G-protein families and their functions

Source: Z. Farfel, H. R. Bourne, and T. Iiri. N. Engl. J. Med. 340(1999):1012.

ClassInitiating signalDownstream signalGs-Adrenergic amines, glucagon, parathyroid hormone, many othersStimulates adenylate cyclaseGiAcetylcholine, -adrenergic amines, many neurotransmittersInhibits adenylate cyclaseGtPhotonsStimulates cGMP phosphodiesteraseGqAcetylcholine, -adrenergic amines, many neurotransmittersIncreases IP3 and intracellular calciumG13Thrombin, other agonistsStimulates Na+ and H+ exchange

Diseases of heterotrimeric G proteins

Source: After Z. Farfel, H. R. Bourne, and T. Iiri. N. Engl. J. Med. 340(1999):1012.

DiseaseExcessive signalingCholeraCancer (adenoma) of pituitary and thyroidCancer (adenoma) of adrenal and ovaryEssential hypertensionDeficient signalingNight blindnessPseudohypoparathyroidism type IbPertussis

Screening of potential drug molecule

Bioinformatics Advance Access published April 25, 2008gpDB: A database of GPCRs, G-proteins, Effectors and their interactions.

Sequence variations in an adrenergic receptor gene cause reduced insulin secretion and contribute to type 2 diabetes.Ratting Out a Diabetes Gene Paula A. Kiberstis Sci. Signal. 3 (104), ec16. [DOI: 10.1126/scisignal.3104ec16]

Methods???