Molecular Fundamentals - Signal Transduction I

what are some of the things that signal transduction are involved in?

• normal physiology

• pharmacology

• cancer

extracellular signals are required for cells to do what?

survive, grow, and divide

extracellular signals also tell a cell when to do what?

differentiate and when to die

what are examples of steroid hormones?

cortisol and estradiol

where to protein/peptide hormones bind?

to cell surface receptors

steroid hormones are what and bind where?

• lipophilic (pass through the plasma membrane unaided)

• to intracellular receptors

what are examples of protein/peptide horomes?

prolactin and adrenocorticotropic hormone (ACTH)

some extracellular signaling molecules promote what?

survival

what is an example of an extracellular signaling molecule involved with survival factors?

cytokines

extracellular signaling molecules can also induce what?

cellular proliferation

extracellular signaling molecules that help with growth factors typically function by activating what?

MAP (Mitogen Activated Protein) kinase cascades

what are examples of extracellular signaling molecules that affect with growth factors?

• IGF-1 (Insulin-like Growth Factor)

• EGF (Epidermal Growth Factor)

• VEGF (Vascular Endothelial Growth Factor)

members of the TGF β Superfamily are involved with what and in what way?

• growth factors

• can be stimulators of cell growth and division

• can be inhibitors of cell growth and division

a disruption of myostatin results in what?

a substantial increase in muscle mass

what describes death signals?

binding of ligand to receptor induces apoptosis in the Fas receptor-expressing cell

what is an example of a death signal?

Fas ligand binds to Fas receptor on nearby cell

what do signal transduction pathways do?

mediate the sensing and processing of external stimuli

what is the first step of signal transduction?

a stimulus induces a secretory cell to release a signaling molecule

what is the second step of signal transduction?

the signaling molecule binds to its receptor on the target cell’s plasma membrane

what is the third step of signal transduction?

binding of signaling molecule to its receptor initiates a signaling cascade inside the cell

what is the fourth step of signal transduction?

the signaling cascade induces a specific response in the cell

what are types of extracellular signaling?

• endocrine

• autocrine

• paracrine

• signaling by plasma-membrane attached proteins

what describes endocrine signaling?

signal-producing cells release signaling molecules that act on distant targe cells

what describes paracrine signaling?

signal-producing cells release signaling molecules that act on proximal targe cells

what is a receptor?

molecule that receives signals from the extracellular environment

what is a ligand?

signaling molecule, selectively binds to a receptor

what are the four major families of cell-surface receptors?

• ligand gated ion channel receptors

• enzyme-coupled receptors

• cytokine receptors

• G-protein coupled receptors

where are ligand gated ion channel receptors found?

on electrically excitable cells (neurons, muscle cells)

ligand gated ion channel receptors transduce what?

a chemical signal into an electrochemical signal

what do GABA_A receptors bind to?

the neurotransmitter Gamma-Amino Butryic Acid

what kind of neurotransmitter is Gamma-Amino Butryic Acid?

an inhibitory neurotransmittor

what does binding of GABA do?

opens the Cl^- channel, allowing for influx of Cl^- and resulting in hyperpolarization of the membrane, which prevents the neuron from firing

Agonists of GABA_a receptors produce what?

sedative effects

binding of acetylcholine (or nicotine) causes what?

a conformational change in the receptor

the conformational change in the receptor after the binding of acetylcholine results in what?

the formation of a pore that allows for Na⁺ ions to enter the cell, allowing for propagation of action potentials

at neuromuscular junctions, activated acetylcholine receptors are responsible for what?

depolarization and subsequent action potentials in postsynaptic cells (muscle cells)

how does termination signal occur for ligand gated ion channel receptors?

ligand is degraded by specific digestive enzymes (proteases) in the synaptic cleft

what is an example of termination of signal for a ligand gated ion channel receptor?

acetylcholine is degraded by acetylchlinesterase

what is the largest family of cell surface receptors?

G-protein coupled receptors

half of all known drugs work through what?

G-protein coupled receptors

what are examples of G-protein coupled receptor signaling?

• adrenergic

• dopamine

• histamine

• serotonin

• prostaglandin

the G-protein complex is composed of what?

α, β, and γ subunits

in a G-protein, what subunit binds to GTP/GDP and possesses GTPase activity?

α subunit

when the α subunit binds to GTP, the protein is what?

on (active)

when the α subunit binds to GDP, the protein is what?

off (inactive)

what does G_αs do?

stimulates adenylyl cyclase

how does stimulation of adenyly cyclase affect cAMP (cyclic AMP)?

increases it

what does G_αi do?

inhibits adenylyl cyclase

how does inhibition of adenyly cyclase affect cAMP (cyclic AMP)?

decreases it

what does G_αq do?

activates phospholipase C

what is the effect of activation of phospholipase C?

stimulates production of inositol triphosphate (IP₃) and diacylglycerol (DAG)

G-protein coupled receptors work through what?

second messengers

what are second messengers?

molecules that relay signals from receptors on the cell surface to target molecules inside the cell

what is an example of a hydrophobic second messenger?

diacylglycerol (DAG)

what are examples of hydrophilic second messengers?

• cyclic AMP (cAMP)

• IP₃ (inositol, 1,4,5-triphosphate)

• calcium (Ca²⁺)

the membrane-associated adenylyl cyclase synthesizes what?

cAMP from ATP

what is the signal termination for cAMP?

the conversion of cAMP into 5’-AMP (done by enzyme cAMP phosphodiesterase)

phospholipase C produces what?

• diacylglycerol (DAG)

• inositol 1,4,5-triphosphate (IP₃)

DAG does what?

serves as a docking site on the plasma membrane for Protein Kinase C (PKC)

what does IP₃ do?

binds to a ligand gated calcium channel receptor on the ER membrane, which causes the calcium channel to open and release calcium into the cytoplasm

together, DAG and Ca²⁺ do what?

activate PKC, resulting in various signaling cascades in the cell

the effects of Ca²⁺ signaling in the cytoplasm is mediated by what?

the binding of Ca²⁺ to calcium-responsive proteins (calmodulin)

the binding of Ca²⁺ to calmodulin (CaM) results in what?

a conformation change in CaM

a conformation change in CaM allows it to do what?

interact with other signaling proteins such as Ca²⁺/Calmodulin-dependent protein kinases (CaMKII)

in smooth muscle cells, muscle contraction requires what?

the activity of MLCK (myosin light chain kinase)

what turns on the kinase activity of MLCK (myosin light chain kinase)?

the binding of Ca²⁺/calmodulin molecules to MLCK (myosin light chain kinase)

an active MLCK can do what?

phosphorylate and activate myosin light chain

once the myosin light chain is activated by MLCK, what happens?

myosin can walk along the actin filaments and produce contraction

what mechanisms in the plasma membrane help maintain low cytoplasmic concentrations of Ca²⁺?

• Na⁺/Ca²⁺ exchanger (antiport)

• Ca²⁺ ATPase pump

what mechanisms in the endoplasmic reticulum membrane (sarcoplasmic reticulum in muscle cells) help maintain low cytoplasmic concentrations of Ca²⁺?

• Ca²⁺ ATPase pump

adrenergic receptors regulate what?

many functions of the autonomic nervous system

adrenergic receptors are considered what?

G-coupled protein receptors

what are the targets of epinephrine/norepinephrine?

adrenergic receptors

what are the two groups of adrenergic receptors?

α and β

the α₁ and α₂ subunits of adrenergic receptors can do what?

either stimulate production of IP₃/DAG/Ca²⁺ or decrease cAMP

the β₁ and β₂ subunits of adrenergic receptors can do what?

increase cAMP

when acetylcholine binds to a muscarinic acetylcholine receptor, what is activated?

G_α and G_β/γ

an activated G_β/γ binds to what?

the intracellular domain of a K⁺ channel, causing it to open

β/γ complex signaling is _______________ of second messengers?

independent

____________ can have different effects depending on the tissue and type of receptor.

acetylcholine

what does acetylcholine bind to in heart muscles?

G-protein coupled receptors (muscarinic acetylcholine receptors)

what leads to opening of K⁺ channels (through G_β/γ proteins), outflow of K⁺, and decreased muscle contraction?

acetylcholine binding to muscarinic acetylcholine recepotrs

in skeletal muscle, what does acetylcholine bind to?

ligand gated ion channel (nicotinic acetylcholine receptors)

what directly opens a Na⁺ channel (influx of Na⁺) and increases muscle contraction?

acetylcholine binding to nicotinic acetylcholine recepotrs

what describes the termination of signal for g-protein coupled receptors?

the α subunit of G-proteins inactivates itself by GTP hydrolysis (takes time, acts as an internal timer)