Cell Communication and Feedback Loops

Cell Communication: Part 1

• The ability of cells to receive and act on signals from outside their plasma membrane is fundamental to life.
• Cellular chemical signaling is complex because of multiple control elements.
• Evolutionarily conserved proteins are used similarly to household items in signaling within cells.
• Elements of chemical-signaling pathways are often highly conserved, and the same molecules are used in different stimulus-response pathways.
• Target cells use different mechanisms to adjust their responses to extracellular signals, with the speed dependent on the turnover of signaling molecules.
• This can cause allosteric change or gene expression.

Feedback Loops

• Negative feedback loops inhibit their own production, Thyroid hormone and temperature regulation are examples.
• Positive feedback loops stimulate their own output/production, blood clot formation, childbirth, fruit ripening, and menstrual cycle are examples.

Signal Transduction - General Properties

• Signal transduction is highly specific and extremely sensitive!

Specificity

• Specificity occurs with precise molecular complementarity between signal and receptor molecules.
• Specific receptors are present in specific cell types in multicellular organisms.

Sensitivity / Amplification

• Affinity is described by the dissociation constant Ka.
• Receptors detect picomolar concentrations of signal molecules.
• Small changes in ligand concentration cause large receptor activation, cooperativity plays a role.
• Enzyme cascades amplify signals: one enzyme activates many of another enzyme, and so on.
• Enzyme cascades can produce amplifications of several orders of magnitude.

Desensitization / Adaptation

• Cells can adjust their sensitivity to a signal.
• Continuous presence of signals can cause desensitization of the receptor system.
• Cell response gets decreased relative to the level of stimulus.
• Receptors can be reactivated if a stimulus falls below threshold.
• Cell can respond to changes in the concentration of an extracellular signal molecule over a wide range of concentrations.

Integration

• Systems can receive multiple signals and produce unified.
• Each cell type is programmed to respond to specific combinations of extracellular signals.
• Each cell type displays a set of receptors that enable it to respond to a corresponding set of signal molecules produced by other cells.

Cell Signaling Mechanisms

• Many types of biological signals have a high degree of conservation in signaling mechanisms during evolution.
• Machinery for transducing signals is built from basic types of protein components.
• These include ligands (first messengers), receptors, G proteins, second messengers, protein kinases, phosphatases, and transcription factors.

Signals Cells Respond To

• Neurotransmitters.
• Hormones (hydrophilic and lipophilic).
• Antigens.
• Cell surface glycoproteins/oligosaccharides.
• Developmental signals.
• Extracellular matrix components.
• Growth factors.
• Mechanical touch
• Light.
• Osmolarity.
• Nutrients.
• Odorants.
• Tastants.
• Pheromones.

Ligands (First Messengers)

• Ligands are endogenous chemicals that enable neurotransmission.
• Amino acids/derivatives/amines: GABA (γ-aminobutyric acid), glutamate, acetylcholine, serotonin, and Catecholamines (dopamine, norepinephrine, epinephrine).
• They transmit signals across a synapse from one neuron to a target neuron, muscle cell, or gland cell.
• Peptides are endorphins and endogenous opioids like (leu-encephalin, met-encephalin, and β-endorphin).
• Atypical (nontraditional) ligands can be found in Gases (NO, CO) and Endocannabinoids.
• Function to change the properties/shape of the receptor.
• From the Latin word ligare, to bind.

More on Ligands

• Binding of a ligand with receptor results in a cellular response.
• Changes in a cell include altering gene transcription or translation, changing cell morphology, and stimulating secretion of a molecule.
• Signal is delivered by binding to a site on a target receptor in ligand-receptor binding.
• These can be from hormone receptors, membrane proteins, or receptors.
• Extracellular signal molecules can act over short or long distances.
• Can originate from different types of molecules like proteins, small peptides, amino acids, nucleotides, steroids, retinoids (Vit. A), and fatty acid derivatives.

Ligand - DNA binding

• The ligand can be an ion or protein that binds to the DNA double helix (epigenetic tags).

Agonists and Antagonists

• Agonists are structural analogs to specific ligands.
• Agonists bind to a receptor and mimic the effects of its natural ligand.
• Antagonists are analogs that bind to the receptor without activating it.
• Antagonists block the effects of agonists, including the natural biological ligand.
• Synthetic agonists or antagonists can have a greater affinity for the targeted receptor than the natural ligand.

Biochemical Signaling

• Intracrine: signals are produced by the target cell.
• Intracrine signals stay within the cell, for example, immune cell growth factor.
• Autocrine: signals are produced by the target cell and are secreted.
• Autocrine signals affect the target cell itself via receptors, for example, immune cells T lymphocytes.
• Paracrine: signals target nearby cells emitting signals, like neurotransmitters, and skin cell's local allergic reaction signals.
• Endocrine: signals target distant cells.
• Endocrine signals are released into the bloodstream, hormones are an example.

Receptors

• Receptors can display high ligand specificity.
• Ligands can exhibit binding versatility, binding to different types of receptors.
• Different cell types can have differentsets of receptors for the same ligand; each set induces a different response.
• The same receptor may occur on various cell types.
• Binding to the same ligand may trigger a different response in each type of cell.
• Ligands are Acetylcholine.
• Ligands are Catecholamines like dopamine, norepinephrine, and epinephrine.

Receptor Locations

• Cell Surface receptors bind to hydrophilic signal molecules .
• Intracellular receptors bind to hydrophobic signal molecules and location of receptor is Cytoplasm or Nucleus.
• Cell Surface receptors are metabotropic or ionotropic.
• Ligand-gated ion channels are triggered by ligand binding activation and openings of the channels.
• Excitatory or inhibitory effects depend on the equilibrium potential of the ion they pass.
• Excitatory ionotropic receptors increase sodium permeability across the membrane.
• Inhibitory ionotropic receptors increase chloride permeability.

Cell Receptors

• G-protein coupled receptors (GPCRs).
• Enzyme-linked (coupled) receptors. Receptor Tyrosine Kinase (RTK), Guanylyl Cyclases, Toll-like receptors, Cytokine receptors,.
• Ligand-gated ion channels.
• Adhesion receptors.

Signal Transducers

• Adhesion receptors: Binds molecules in extracellular matrix, changes conformation, thus altering its interaction with cytoskeleton.
• Gated ion channel: Opens or closes in response to concentration of signal ligand or membrane potential.
• Nuclear receptor: Steroid binding allows the receptor to regulate the expression of specific genes.
• Receptor guanylyl cyclase: Ligand binding to extracellular domain stimulates formation of second messenger cyclic GMP.
• Receptor tyrosine kinase: Ligand binding activates tyrosine kinase activity by autophosphorylation.
• G protein-coupled receptor: External ligand (S) binding to receptor (R) activates an intracellular GTP-binding protein (G), which regulates an enzyme (Enz) that generates an intracellular second messenger, X.

Second Messengers

• Signaling molecules generated in large amounts in response to receptor activation.
• Diffuse away from their source and spread the signal to other parts of the cell.
• They bind to and alter the behavior of selected signaling or effector proteins.

Types of Second Messengers

• The types of are diacylglycerol (Hydrophobic), cAMP, cGMP, IP3, Calcium (Hydrophilic), NO, and H2S (Gases).
• Few second-messenger systems exist within animal cells.
• DIACYLGLYCEROL (DAG) is hydrophobic.
• It's a plasma membrane-associated lipid that can regulate membrane-associated effector proteins.
• INOSITOL 1,4,5-TRISPHOSPHATE (IP3), CYCLIC ADENOSINE MONOPHOSPHATE (cAMP), and CALCIUM (Ca2+) are water-soluble molecules acting within the cytosol.

Molecular Switches

• Proteins act as intracellular signaling molecules by activating another protein in a signaling pathway.
• Proteins can switch between active and inactive states, acting as molecular switches in response to another signal.
• External signals may flip the molecular switch could be protein kinase or protein phosphatase.
• Protein kinase adds phosphate group to the protein.
• Protein phosphatase removes phosphate groups.
• When receiving a signal, they switch from an inactive to an active state until another process switches them off.
• Very important in the intracellular signaling pathway.