Introduction to Receptors 1 a a b g

�Receptors are protein molecules in the target cell or on its surface that bind ligands. �Receptors, either intracellular or cell-surface, bind to specific ligands, which activate numerous cellular processes. �Receptors receive chemical signals that give commands to the Allow this cell. molecule to pass Divide

Key Terms �integral protein: a protein molecule (or assembly of proteins) that is permanently attached to the biological membrane �transcription: the synthesis of RNA under the direction of DNA

Internal Receptors �Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. �Once inside the cell, many of these molecules bind to proteins that act as regulators of m. RNA synthesis to mediate gene expression. �Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids that ultimately forms a protein.

�When the ligand binds to the internal receptor, a conformational change exposes a DNA-binding site on the protein. �The ligand-receptor complex moves into the nucleus, binds to specific regulatory regions of the chromosomal DNA, and promotes the initiation of transcription. �Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or

Class 1: Intracellular receptors �Can be divided into 2 general groups �Nuclear and cytoplasmic Cell membrane nucleus DNA

�Cytoplasmic – in the cytoplasm of cell �Ligand binds… Cell membrane nucleus m. RNA • Receptor crosses the nucleus through a pore • Binds to DNA, enhances transcription • New messenger RNA leaves nucleus DNA

�Nuclear – in the nucleus of cell �Ligand binds… Cell membrane nucleus m. RNA • Receptor bound to DNA, enhances transcription • New messenger RNA leaves nucleus DNA

Cell-Surface Receptors �Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. �This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. �Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

�Each cell-surface receptor has three main components: an external ligandbinding domain (extracellular domain), a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. �The size and extent of each of these domains vary widely, depending on the type of receptor. �Cell-surface receptors are involved in most of the signaling in multicellular organisms.

Class I 1: Cell Surface Receptors �Can be divided into several categories a b N C Ligandgated Ion channels a g b G-protein coupled receptors Integrins Receptor tyrosine kinases Toll-like receptors

�There are three general categories of cell-surface receptors: ◦ Ion channel -linked receptors bind a ligand open a channel through the membrane that allows specific ions to pass through. ◦ G-protein-linked receptors bind a ligand activate a membrane protein called a G-protein, which then interacts with either an ion channel or an enzyme in the membrane. ◦ Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme.

Ligand gated Ion channels � Gated ion channels form a pore through the plasma membrane that opens when the signaling molecule binds. The open pore then allows ions to flow into or out of the cell.

Ligand gated Ion channels Pentamers – 5 subunits subunit pore subunit Cell membrane

Ligand gated Ion channels Activated or turned on by are molecules that act like keys that fit certain binding pockets or locks on the receptor. Cell membrane

Ligand gated Ion channels When the ligand binds, the subunits undergo changes opening the pore ion Cell membrane � Ions such as Na+, K+, Ca+2, and Clthen flow down their electrochemical gradient into the cell

Examples of these: �GABA �Glycine �Nicotinic acetylcholine �Serotonin �Glutamate

G-Protein Linked Receptors �G-protein-linked receptors bind a ligand activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane. �All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-proteinbinding site.

G-protein coupled receptors • G-protein composed of one alpha, beta, and gamma subunit • 2 primary signaling cascades: c. AMP or phosphatidylinositol pathways Cell membrane a g b • Pathway activated depends on alpha subunit type

G-protein coupled receptors • When a ligand binds, the receptor changes conformation, allowing G-protein to be activated (GDP is exchanged for GTP) • G-protein dissociates from receptor then subunits from each other. Cell membrane a GTP g b

c. AMP pathway AC a GTP c. AMP g b ATP Cell membrane

Phosphatidylinositol pathway PIP 2 a GTP g PLC b P P P GTP To sarcoplasmic

6 Major classes of these �Class A (or 1) (Rhodopsin-like) �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)

Receptor tyrosine kinase • Two inactive monomers contain tyrosine (Tyr) residues • Ligand binding to the monomers leads to dimer formation Cell membrane Tyr Tyr Tyr

Receptor tyrosine kinase ATP molecules donate a phosphate (P) to each of the tyrosines. Inactive relay proteins bind to the phosphorylated tyrosine residues and trigger cellular responses downstream Cell membrane ATP P Tyr Tyr P ATP P

Examples of these: �Insulin �Vascular Endothelial Growth Factor (VEGF) �Platelet-derived Growth Factor (PDGF) �Epidermal Growth Factor (EGF) �Eph

Integrins a • Join the cytoskeleton on the inside of the cell to the extracellular matrix on the outside. • Heterodimers of alpha and beta subunits b Cell membrane

Examples of these: �Ligands in ECM – collagen, fibronectin, and laminin �Important for cellular processes including: cell adhesion, cell migration, signal transduction, and cell growth/death

Toll-like receptors Cell membrane nucleus • Involved in the immune response • Signals between downstream proteins result in enhanced transcription of inflammatory Immune response DNA

Examples of these: �Ligands include: Lipopolysaccharide, double-stranded RNA, flagellin, heat shock proteins �Important for the innate immune response to bacterial and viral stimuli.