Biochem Ch 12

biosignaling

importance and advantages of cell signaling

responding to changes in environment; coordination and homeostasis; biological regulation

examples of coordination and homeostasis

metabolism, growth, development, reproduction

signal transduction (cell signaling, biosignaling)

transmitting molecular signals from environment to interior of cell (need something to continue signal, molecule cannot enter cell)

examples of environmental signals

antigens, light, hormones, odorants, neurotransmitters

ways signals cause changes in cell’s composition and function

differentiation and antibody production; growth in size, shape, or strength; gene expression; ability to divide

major types of cell signaling

autocrine, paracrine, endocrine

autocrine signaling

acting on same cell (that produces signal)

paracrine signaling

acting on nearby cell

endocrine signaling

carried in bloodstream to distant target cell (gland usually involved)

essential steps of cell signaling

signal reception, signal transduction, cellular response

signal reception

signal binds to receptor (temporarily), often located on cell surface

signal transduction

signal binding changes receptor (conformation or shape); change initiates conversion of signal to specific cellular response

cellular response

actual cellular response that is triggered (like enzyme activation or altered gene expression)

receptor

membrane bound or soluble protein, or protein complex that exerts physiological effect after binding ligand

types of receptors

G-protein coupled receptors (GPCR), enzyme linked receptors, ligand gated ion channels (main cell surface receptors), nuclear receptors (receptor inside cell), other membrane receptors

example of GPCR

epinephrine receptor

example of enzyme linked receptor

insulin receptor

example of ligand gated ion channel

nicotinic acetylcholine receptor

example of nuclear receptor

steroid receptor

example of other membrane receptor

integrin receptor

features of signal transducing systems (8)

specificity, sensitivity, amplification, modularity, desensitization (adaptation), integration, divergence, localized response

typical ligands

small ions, organic molecules, polysaccharides, peptides, proteins

considerations for receptors

weak interactions, if receptor is cell specific, high affinity for signal, cooperativity and clustering (lipid rafts and avidity)

cooperativity consideration in receptors

how will multiple binding sites influence binding affinity

avidity

clustering helps activate signals when affinity is weak (sum of signal effects makes overall signal stronger)

specificity

how specific a receptor (protein) is for a signal (ligand)

sensitivity

how well the receptor binds to the signal (high affinity/ low Kd)

amplification

more activated enzymes creates a stronger signal

modularity

the same signal can produce different responses in multiple/ different targets (ex heart and liver)

desensitization/ adaption

receptor activation turns off pathways (or removes receptor from cell surface)

integration

two different receptors/signals have opposite effects; the result is a net change/ response

divergence

one signal/ receptor activates multiple pathways with different effects

localized response

signal is degraded before it can diffuse, so response is local and brief

crosstalk

allows integration of multiple signals (several receptors can be activated at the same time)

major types of signal transducers

GPCR, receptor enzyme, gated ion channel, nuclear receptor

GPCR (general)

7 pass a-helical integral membrane protein; heterotrimeric (3 parts: aBy); bind GTP/GDP; stimulatory or inhibitory response; mediate signal transduction to other target proteins

epinephrine production location and purpose

adrenal glands; mediates stress response by mobilizing energy

ways adrenal glands mobilize energy (muscle/liver, adipose, heart)

binding to receptors in muscle/liver to induce breakdown of glycogen; binding to receptors in adipose cells to induce lipid hydrolysis; binding to receptors in heart cells to increase heart rate

G protein receptor in epinephrine

B-Adrenergic receptor

effector and it’s role in epinephrine signaling

Adenylyl cyclase (effector) is an enzyme that converts ATP to cAMP

1st step in epinephrine pathway

epinephrine binds to B-Adrenergic receptor

2nd step in epinephrine pathway

allosteric change in hormone-receptor complex causes the GDP bound to Gsa to be replaced by GTP, activating Gsa

3rd step in epinephrine pathway

activated Gsa separates from GsBy, then moves to adenylyl cyclase and activates it

4th step in epinephrine pathway

adenylyl cyclase catalyzes the formation of cAMP (from ATP)

5th step in epinephrine pathway

cAMP diffuses into cytoplasm and activates PKA

6th step in epinephrine pathway

phosphorylation of cellular proteins by PKA causes the cellular response to epinephrine

7th step in epinephrine pathway

cAMP is degraded (by cyclic nucleotide phosphodiesterase), reversing the activation of PKA

what influences the function of a trimeric G protein

the nucleotide it is bound to

intrinsic rate of hydrolysis

the GTP bound to an active a-protein will lose a phosphate group over time (naturally converts to GDP)

examples of effectors

other enzymes, AC, ion channels

enzyme that converts cAMP to AMP

cyclic nucleotide phosphodiesterase

role of cAMP

activates cAMP-dependent protein kinase A (PKA)

role of PKA

activates enzymes that produce glucose from glycogen

protein kinases (general)

enzymes that catalyze the phosphorylation of Ser, Thr, or Try hydroxyl groups in target proteins (add Pi to their OH)

how protein kinases determine what to target (target selection)

target protein has an amino acid sequence that is recognized by kinase

number of cAMP needed to activate PKA

4 total (2 for each regulatory subunit)

how cAMP activates PKA

cAMP binds to regulatory domains, causing a shape change; catalytic domains disassociate and can no longer bind to reg domains

purpose of anchor/scaffold protein (AKAP)

keeps PKA local to specific structures

where amplification happens in epinephrine pathway

making cAMP from ATP

how to turn epinephrine pathway off (self inactivation)

downregulate cAMP levels with intrinsic rate of hydrolysis, or cyclic nucleotide phosphodiesterase

GEF (guanine exchange factor)

anything that helps (alpha) exchange GDP for GTP

GAP (GTPase activating protein)

increase the rate of GTP hydrolysis

desensitization in epinephrine pathway

binding epinephrine to receptor triggers dissociation of GsBy from Gsa; GsBy recruits BARK to the membrane, where it phosphorylates Ser residues at the carboxyl terminus; Barr binds to the prosphorylated carboxyl terminal domain; receptor-arrestin complex enters the cell in endocytosis

agonist

substrate that binds to a receptor to mimic the effect and shape of the natural ligand (stimulate a pathway)

antagonist

substrate that binds to a receptor without triggering the natural effect (inhibits pathway)

what morphine is an example of

an agonist for some opioid receptors (but desensitization requires higher dosages)