3 - Cell Signaling

signal transduction

process by which one type of signal is converted into another

paracrine signals

released by cells into the EC fluid and act locally

neuronal signals

transmitted electrically along an axon, when it reaches a terminal: causes release of neurotransmitters onto adjacent target cells

contact dependent signaling

• cell surface bound signal molecule binds to a receptor protein on adjacent cell

large, hydrophilic EC signal molecules

• can not cross plasma membrane directly

• bind to cell surface receptors that generate 1+ IC signaling molecules in target cell

small, hydrophobic EC signal molecules

• pass through plasma membrane

• bind to IC receptors in cytosol or nucleus

• regulate gene transcription or other functions

EC signals: cell differentiation or increased cell growth/division

• changes in gene expression & synthesis of new proteins

• occur slowly

EC signals: changes in cell movement, secretion, metabolism

• no changes in gene expression

• occur faster

Intracellular signaling pathways:

• relay signal and help it spread through cell

• amplify signal & make it stronger so fewer signaling molecules have stronger effects

• integrate signals from multiple pathways

• distribute to more than one effector protein to evoke complex responses

• feedback regulation of upstream signaling parts

positive feedback

downstream component of pathway enhances the response of initial signal

negative feedback

downstream part of pathway diminishes response of upstream signal

protein phosphatases

remove phosphates to deactivate effector protein following removal of signal

GTP binding proteins

• switch IC pathways on and off

• close to cell membrane

• proteins active upon binding GTP

• proteins inactive by hydrolyzing GTP to GDP

GEFs (guanine nucleotide exchange factors)

activate monomeric GTPase proteins by promoting exchange of GDP for GTP

GAPs (GTPase activating proteins)

turn off monomeric GTPase proteins by stimulating hydrolysis of GTP to GDP

ion channel coupled receptor/transmitter-gated ion channel

• opens in response to binding an EC signal molecule

• changes the membrane potential of cell to make electrical current

• rapid transmission of signals across synapses

• transduce chemical signals (neurotransmitter) into electrical signals

• channels open up allowing ions (Na+ K+) to flow in or out of cells (electrochemical gradients)

• common in heart and neurons

G protein coupled receptors

• activate membrane bound trimeric GTP binding proteins

• proteins then activate intracellular enzymes or also ion channels in the plasma membrane to stimulate an IC signaling cascade

enzyme coupled receptors

• act like enzymes or associate w/ them

• upon stimulation by a ligand, the enzymes activate a variety of IC signaling pathways

3 types of cell surface receptors

ion channel coupled receptor, G protein coupled receptor, enzyme coupled receptor

GPCR structure

single polypeptide with 7 transmembrane domains and an intracellular tail (c-terminal)

GPCR disease —> Cholera Toxin

• infects human intestine

• modifies the a subunit of the G protein

• GTP cannot turn into GDP so increased activation of a subunit

• stimulation of effector proteins (adenylyl cyclase)

• impairs Cl- trafficking causing excessive water to flow into gut

GPCR disease —> pertussis toxin

• infects the lung

• modifies the a subunit of the Gi protein

• GDP cannot turn to GTP which inactivates Gi protein

• Gi normally inhibits adenylyl cyclase

• excessive, prolonged activation

cAMP (2nd messenger)

• made by adenylyl cyclase

• degraded by cAMP phosphodiesterase

• cAMP is formed from ATP via cyclization rxn that removes two phosphate grps from ATP and joins the free end of the remaining phosphate group to the sugar part of the AMP molecule

• degradation by cAMP phosphodiesterase breaks the new bond, forming AMP

• caffeine inhibits AMP phosphodiesterase & helps maintain high conc of cAMP

cyclic AMP-dependent protein kinase (PKA)

• normally kept in an inactivated state by a protein complex

• cAMP binds the regulatory complex, releasing PKA

• PKA phosphorylates & modulates the activity of IC signaling proteins

• ex. epinephrine stimulates glycogen breakdown in skeletal muscle

rise in intracellular cAMP….

activates gene transcription

• activates PKA, allowing it into the nucleus to phosphorylate transcription regulators

• once phosphorylated, these proteins stimulate the transcription of target genes