The Need to Communicate Part 2 (Cell Signaling) PDF

15/10/23 The need to communicate: part 2 Cell surface receptor: A typical cell-surface receptor has three different domains, or protein regions: am extracellular ligand-binding domain, a hydrophobic domain and an intracelluar domain ( which often transmits a signal ). The size and structure of these...

15/10/23 The need to communicate: part 2 Cell surface receptor: A typical cell-surface receptor has three different domains, or protein regions: am extracellular ligand-binding domain, a hydrophobic domain and an intracelluar domain ( which often transmits a signal ). The size and structure of these regions can vary a lot depending on receptor type, and the hydrophobic region may consist of multiple stretches of amino acids that criss-cross the membrane. Cell surface receptors are membrane-anchored proteins that bind to ligands on the outside surface of the cell. In this type of signalling, the ligand doesn’t need to cross the membrane. So, many different molecules ( including large hydrophilic ) may act as ligands. What are GPCRs: These are a large family of cell surface receptors that share a common structure and method of signalling. The members of the GPCR family all have seven different protein segments that cross the membrane, and they transmit signals inside the cell through a type of protein called a G protein. When its ligand isn’t present, a GPCR waits at the plasma membrane in an inactive state. For at least some types of GPCRs, the inactive receptor is already docked to its signalling target, a G-protein. G-proteins come in different types, but they all bind the nucleotide GTP, which they can break down to form GDP. A G-protein attached to the GTP is active, while a G-protein attached to GDP is inactive. The G-proteins that associate with GPCRs are a type made up of three subunits, known as heterotrimeric G proteins. When they’re attached to an inactive receptor, they’re in the off form ( bound to GDP ). Types of GPCRs: 1 Gs 2 Gi 3 Gq stimulates Inhibits Activates adenylate adenylate phospholipase cyclase cyclase c cAMP as a second messenger: Receptor Tyrosine kinases: Enzyme linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor actually is an enzyme. Other enzyme-linked receptors have an intracellular domain that interacts with an enzyme. Receptor tyrosine kinases ( RTKs ) are a class of enzyme-linked receptors found in humans and many other species. A kinase is just a name for an enzyme that transfers phosphate groups to a protein or other target, and a receptor tyrosine kinase transfers phosphate groups speci cally to the amino acid tyrosine. How does RTK signalling work: In a typical example, signalling molecules st bind to the extracellular domain of t wo nearby receptor tyrosine kinases. The t wo receptors then come together or dimerise to form a dimer. The receptors then attach phosphates to tyrosines in each other’s intracellular domains. The phosphorylated tyrosine can transmit the signal to other molecules in the cell. Example: insulin receptor Step 1 2 is Step I to 6 on above diagram Intracellular receptors: Intracellular receptors are receptor proteins found on the inside of the cell, typically in the cytoplasm or the nucleus. In most cases, the ligands of intracellular receptors are small, hydrophobic molecules, since they must be able to cross the plasma membrane to reach their receptors. For example, the primary receptors for hydrophobic steroid hormones. Nuclear receptors: Hormones like the steroid hormones are lipid soluble and can diffuse through the phospholipid bilayer. Inside the cell they bind to their receptors, causing a conformational change. The conformational change allows a dimer to form. The dimer can then enter the nucleus The dimer binds to recognition sites on DNA and triggers or inhibits transcription of speci c genes. Endocrine signalling: Types of hormones: Amino acid derivatives Steroids Peptides Proteins Glycoproteins Amino acid derivatives: Adrenaline and noradrenaline. These are known as the catecholamines, they circulate freely or weakly bound to albumin in the blood. They have a short half life and bind to GPCRs. Thyroid hormones (T3 and T4). Circulate bound to plasma proteins. Long half lives. Transported through membranes and bind to nuclear receptors. Steroids: Estrogens, androgens aldosterone etc. They circulate bound to plasma proteins, but readily diffuse through cell membrane. Bind to intracellular steroid receptors. All have cholesterol as the basis of their structure. Peptides, proteins and glycoproteins: Are usually carved from prohormones when needed. Then are secreted by exocytosis and don’t usually bind to plasma proteins. They are very different in structure so their effects are mediated by several different mechanisms. Learn these: Peptide hormones: Protein hormones: Thyrotropin releasing factor ( TRH ) Gonadotrophin releasing hormone ( GnRH ) Adrenocorticotropic hormone ( ACTH ) ADH Oxytocin Glucagon Somatostatin Vasoactive intestinal polypeptide ( VIP ) Paracrine and autocrine: Paracrine means that a cell’s target cell is next to it. Autocrine means the cell secretes a hormone and that hormone is acting on a receptor itself. Insulin Insulin-like growth factors ( IGFs ) Prolactin ( PRL ) Growth hormone ( GH ) Placental lactogen ( PL ) Parathyroid hormone ( PTH ) Examples: Paracrine: Nitric oxide. This is a local vasodilator released from endothelial cells. Autocrine: Prostaglandins. These are in ammatory mediators. Direct communication: Tight junctions: prevents Desmosomes: joins cells Gap junction: allows communications Tight junctions: Tight junctions: Form a belt around the cell, anchoring it to the neighbouring cell Not attached to the cytoskeleton unlike Desmosomes The belt stops membrane proteins moving past and stops molecules diffusing across the tissue. Fence and gate functions of tight junctions: A. The tight junction can function as a gate by regulating paracellular transport bet ween cells. ( red X on diagram ). B. The tight junction can also act as a fence, preventing apical cell membrane proteins from transporting to the basolateral surface and vice versa ( red X ) Paracrine vs juxtacrine: Gap junctions: These are channels or bridges bet ween cells formed from Connexins They allow small molecules and ions to pass bet ween cells So small chemical and electrical signals can pass through them This is how electrical signals pass through smooth muscles Desmosomes: They anchor cells together and are attached to the cytoskeleton Cadherins form the links bet ween the plaques in the individual cells Bystander effect in cells: cells Surroundingeven effected though not hit with a particle a particle f radiotherapy