Introduction to Signal-Transduction Pathways
Introduction to Signal-Transduction Pathways
Based on Chapter 14 of Biochemistry by Jeremy M. Berg, Gregory J. Gatto, Jr., Justin K. Hines, John L. Tymoczko, Lubert Stryer.
Tenth Edition, Macmillan Learning.
Signal Transduction Learning Goals
By the end of this chapter, you should be able to:
Identify the essential features of a signal-transduction circuit.
Identify what is meant by a second messenger and identify examples.
Recognize and analyze example signaling systems (adrenergic receptor, insulin receptor, and epidermal growth factor receptor) to identify the primary signaling molecule (signal), receptor (transducer), second messenger (effector), and mechanisms of signal termination.
Identify the "net effects" of each intracellular signaling cascade covered in the examples.
Explain how the senses of smell and vision transmit information via signal-transduction pathways (note: hearing is not covered).
Chapter 14 Outline
14.1 Many Signal-Transduction Pathways Share Common Themes
14.2 Epinephrine Signaling: Heterotrimeric G Proteins Transmit Signals and Reset Themselves
14.3 Insulin Signaling: Phosphorylation Cascades Are Central to Many Signal-Transduction Processes
14.4 Epidermal Growth Factor: Receptor Dimerization Can Drive Signaling (14.5 concepts later in PharmD curriculum!)
14.6 Sensory Systems Are Based on Specialized Signal-Transduction Pathways
Section 14.1: Many Signal-Transduction Pathways Share Common Themes
Signal transduction pathway: A chain of events that converts extracellular messages into a physiological response.
Transduction: The conversion of information, signaling molecules into a “downstream” molecular physiological message.
Components of a Signal-Transduction Pathway:
SIGNAL: Can be a hormone or neurotransmitter.
TRANSDUCER: Typically a receptor or ion channel.
EFFECTOR: Typically a second messenger.
Signal Transduction Works via Molecular Circuits
Key Steps in Signal-Transduction Pathways:
Release of the primary messenger (the signal).
Reception of the primary message by a receptor, usually a membrane protein with extracellular and intracellular components.
Delivery of the message inside the cell by intracellular second messengers.
Activation of other molecules which alter the physiological response.
Termination of the signal to reset the system.
Signal-Transduction Pathway Specificity
The specificity of signal transduction pathways operates similarly to the "lock-and-key" model of substrate binding to enzymes.
Signal molecules bind specifically by complementarity to a receptor.
Agonist: A molecule that, upon binding, stimulates the downstream signaling.
Antagonist: A molecule that, upon binding, inhibits the downstream signaling.
Can bind to either direct or allosteric sites.
Changes in Signals Lead to Responses
Changes in signals (represented by red arrows in visual aids) lead to pathways that promote feedback regulation (blue arrows) to restore homeostasis.
Common Second Messengers (Effectors)
Examples of common second messengers include:
Cyclic AMP (cAMP)
Cyclic GMP (cGMP)
Calcium ions (Ca$^{2+}$)
Inositol 1,4,5-trisphosphate (IP3)
Diacylglycerol (DAG)
Consequences of Second Messengers
The activation of second messengers may significantly amplify the signal.
They often freely diffuse and influence processes throughout the cell.
The use of common second messengers in multiple signaling pathways creates cross-talk among cellular signals.
Example Pathways Illustrating Signal Transduction Principles
Epinephrine Signaling: Associated with fight-or-flight responses and muscle contraction.
Insulin Signaling: Responsible for glucose uptake and storage in cells.
Epidermal Growth Factor (EGF): Stimulates growth-promoting gene expression.
Seven-Transmembrane-Helix (7TM) Receptors
A large class of cell-surface receptors that transmit diverse signals initiated by hormones, neurotransmitters, odorants, and light.
These receptors frequently serve as therapeutic drug targets and contain seven helices that span the cell membrane.
Ligand Binding to 7TM Receptors Leads to G Protein Activation
When a ligand binds to a 7TM receptor, it induces a conformational change on the cytoplasmic side that activates a G protein.
The activated G protein stimulates adenylate cyclase, which catalyzes the conversion of ATP into cAMP.
Activation of Heterotrimeric G Proteins
In its inactive state, the G protein exists as a heterotrimer with α, β, and γ subunits.
The α subunit (Gα) is associated with GDP.
When activated by a receptor, Gα exchanges GDP for GTP, active switching to its signaling form.
Upon binding GTP, Gα dissociates from Gβγ, activating downstream signaling pathways.
G Proteins Spontaneously Reset Themselves
Gα subunits promote the hydrolysis of bound GTP to GDP and Pi via intrinsic GTPase activity.
The hydrolysis process is slow (seconds to minutes), allowing for downstream activation before resetting.
Following hydrolysis, Gα reassociates with Gβγ to form the inactive heterotrimeric protein once more.
Termination of β-Adrenergic Receptor Signaling
Resetting the hormone-bound activated receptor can occur through:
Hormone dissociation from the receptor.
G-protein receptor kinases phosphorylating serine and threonine residues on receptors, followed by β-arrestin binding, thereby blocking receptor activation of G proteins.
Phosphoinositide Cascade Activated by Some 7TM Receptors
α-adrenergic receptors: Activate Gαq, which activates phospholipase C.
Phospholipase C cleaves PIP2 into IP3 and DAG, generating additional second messengers.
Inositol 1,4,5-Trisphosphate (IP3) and Diacylglycerol (DAG)
IP3 causes Ca$^{2+}$ release from the endoplasmic reticulum (ER).
Calcium ions serve as rapid signaling molecules and can activate calcium-binding proteins.
DAG, remaining in the membrane, activates protein kinase C (PKC).
Calcium Ions and Calmodulin
Calmodulin is a common calcium-binding regulatory protein that undergoes conformational changes upon binding Ca$^{2+}$, allowing it to activate various proteins, including kinases.
Insulin Signaling: Central Role of Phosphorylation Cascades
Insulin: Released in response to high blood glucose, facilitates glucose uptake by promoting translocation of glucose transporters to cell surfaces.
Insulin Receptor Structure and Activity
The insulin receptor exists as a homodimer with α and β chains.
The α chain is extracellular, while the β chain has a domain that functions as a tyrosine kinase.
Cross-Phosphorylation of Insulin Receptor Kinase
Insulin binding initiates conformational changes that lead to receptor autophosphorylation.
Phosphoinositide 3-Kinase (PI3K) Function in Insulin Signaling
PI3K converts PIP2 into PIP3, aiding recruitment of signal molecules necessary for downstream signaling.
Net Effects of Insulin Signaling
Insulin's binding promotes increased glucose transporter presence on cell surfaces.
Insulin Signaling Termination Mechanisms
Internally through phosphatases that remove phosphorylation from active sites, leading to signal termination.
Epidermal Growth Factor (EGF) and EGF Receptor Signaling
EGF stimulates cell growth and healing by binding to its receptor, leading to receptor dimerization and subsequent Ras activation.
Signaling Cascade Initiated by EGF Binding
EGF activation of Ras initiates a signaling cascade involving the phosphorylation of transcription factors and kinases in the nucleus, promoting various cellular growth processes.
Termination of EGF Signaling
EGF signal termination occurs through phosphatases that remove phosphoryl groups, Ras's intrinsic GTPase activity, and the action of GTPase-activating proteins (GAPs).
Defects in Signal-Transduction Pathways and Cancer
Mutations in genes encoding signal transduction proteins, such as Ras, are linked to various cancers, often leading to loss of regulation or overexpression of certain pathways.
Sensory Systems and Signal Transduction Pathways
Specific odorants activate certain receptors in the olfactory system, with about 400 different receptors present in the human genome.
Visual Signal Transduction via Rhodopsin
Rhodopsin is responsible for vision by absorbing light and initiating a signaling cascade through transducin activation, which ultimately leads to nerve impulses.