Definition: Signal transduction is the process by which a cell converts an external signal into a specific internal response.
Steps Involved:
Reception: A ligand binds to a receptor on the cell surface.
Transduction: The signal is relayed and amplified inside the cell.
Response: The cell executes a specific action based on the received signal.
Signal Molecule Interaction
Non-Entering Ligand: A signal molecule (ligand) binds to a membrane receptor, causing a conformational change in the receptor, which activates intracellular signaling pathways. The ligand does not enter the cell.
Ligand Types
Extracellular Ligand:
Remains outside the cell and binds to integral membrane proteins (e.g., peptide hormones).
Cytoplasmic Ligand:
Composed of small or nonpolar molecules that diffuse across the cell membrane and bind inside the cell (e.g., steroid hormones like testosterone).
Receptor-Ligand Interactions
Characteristics:
Highly specific interactions, resembling enzyme-substrate interactions.
Shape compatibility: Often described as a "lock-and-key" fit.
Binding: Primarily non-covalent interactions including hydrogen and ionic bonds.
Ligand binding triggers conformational changes in the receptor, similar to enzymatic reactions.
Levels of Signaling
Local Signaling:
Paracrine: Affects nearby cells.
Autocrine: Affects the same cell that secreted it.
Long Distance Signaling:
Endocrine: Hormonal signals travel via the bloodstream to distant target cells.
Paracrine vs. Endocrine Hormones
Paracrine Hormone: Short-distance signaling acts on nearby cells.
Endocrine Hormone: Travels through the bloodstream and acts on distant cells.
Signal Amplification
Definition: Enables a small number of ligands to activate a large number of intracellular molecules.
Significance:
Produces a strong internal response from a tiny external signal.
Enhances the speed and magnitude of cellular responses.
G-Protein-Coupled Receptors (GPCRs)
Structure:
Consists of 7 transmembrane alpha-helices.
Contains a ligand-binding domain (extracellular) and a G-protein interaction domain (intracellular).
Function: Upon ligand binding, GPCRs activate G-proteins within the cell.
G-Proteins
Structure:
Composed of three subunits: alpha (α), beta (β), and gamma (γ).
β and γ are tightly associated while α can detach when activated.
Activation Cycle:
GDP-bound α is inactive; GTP-bound α is active.
Mechanisms of G-Protein Signal Transduction
Ligand binds to GPCR.
GPCR undergoes conformational change.
GPCR activates G-protein by exchanging GDP for GTP on the α subunit.
The activated α subunit dissociates from the βγ complex and interacts with target proteins (e.g., adenylyl cyclase).
cAMP: A Second Messenger
Definition: Cyclic AMP (cAMP) is a second messenger involved in various signaling pathways.
General Pathway:
Active Gα activates adenylyl cyclase.
Adenylyl cyclase converts ATP to cAMP.
cAMP activates protein kinase A (PKA).
PKA phosphorylates target proteins leading to a cellular response.
cAMP Regulation
Adenylyl Cyclase: Produces cAMP when activated by Gα-GTP.
cAMP Phosphodiesterase: Degrades cAMP to AMP, terminating the signal.
Key Enzyme Definitions
Kinase: Adds a phosphate group to a molecule using ATP.
Phosphorylase: Adds inorganic phosphate without using ATP.
Phosphatase: Removes a phosphate group from a molecule.
Glycogen Metabolism Pathways
Glycogenesis (Synthesis):
Converts glucose to glucagon for storage.
Glycogenolysis (Breakdown):
Converts glycogen back to glucose for energy.
Regulation of Glycogen Phosphorylase
Mechanism: Activated by phosphorylation via PKA.
Forms:
Inactive: phosphorylase b (unphosphorylated)
Active: phosphorylase a (phosphorylated)
Fight or Flight Response via Epinephrine
Epinephrine binds GPCR on liver/muscle cells.
GPCR activates Gα protein.
Gα activates adenylyl cyclase.
Adenylyl cyclase increases cAMP production.
cAMP activates PKA leading to phosphorylation of key enzymes.
IP3/DAG Signaling Pathway
Activation: Phospholipase C (PLC) activated by G-protein or RTK cleaves PIP2 forming IP3 and DAG.
Effects:
IP3 releases Ca2+ from the ER.
DAG activates protein kinase C (PKC).
Calcium Signaling
Basal levels of cytoplasmic [Ca2+]: ~10^-4 mM (low).
[Ca2+] in ER/Extracellular: Higher than cytoplasm to control signaling.
Calmodulin: A small protein with four binding sites for Ca2+. Changes conformation when Ca2+ binds, regulating other proteins.
Blood Vessel Structure
Inner Layer: Endothelium (composed of endothelial cells).
Middle Layer: Smooth muscle cells.
Outer Layer: Connective tissue (collagen and elastin fibers).
Vasodilation vs Vasoconstriction
Vasodilation: Relaxation of smooth muscle, resulting in vessel widening.
Vasoconstriction: Contraction of smooth muscle, leading to vessel narrowing.
Steps Involved in Calcium-Mediated Vasodilation
Signal molecule binds to endothelial cells.
Production of IP3 leads to Ca2+ release from the ER.