NSC 300 - Ch 7: Signal Transduction

types of molecular signaling

1. synaptic

2. paracrine

3. endocrine

4. cell-cell interactions

5. diffusible signals

synaptic signaling

• chemical signaling

• transfers info from 1 neuron to another

• intimate association of pre- & post-synaptic cells

• short range, direct

paracrine signaling

• secretion of chemicals over a short range

• stimulates multiple cells in an area

• longer than synaptic transmission

endocrine signaling

• systemic circulation of signal

• targets cells throughout organism

• secretion of hormones into bloodstream (affect targets throughout body)

cell-cell interactions

• 3 types

  • cell - impermeant molecules

  • cell - permeant molecules

  • cell - associated molecules

• proteins interact at surface of the cell

• cell-association signals

• important in development & neurite growth

cell - impermeant molecules

• these can’t readily traverse the plasma membrane of the target cell & must bind to the extracellular portion of transmembrane receptor proteins

• signaling molecules

  • polar/charged - can’t cross lipid bilayer

    • bind to receptors on surface of cell

cell - permeant molecules

• these are able to cross the plasma membrane & bind to the receptor proteins

• ex: steroid hormones (hydrophobic) → bind to receptors inside cell

• nitric oxide & endocannabinoids

• small, nonpolar. molecules

cell - associated molecules

• requires direct contact b/w the 2 cell types

• these are presented on the extracellular surface of the plasma membrane

• these signals activate receptors on target cells only if they are directly adjacent to the signaling cell

diffusible signals

• released from 1 cell & travel through extracellular space

• includes NTs, hormones, other molecules

• can be cell - impermeant or cell - permeant

Channel - linked receptors

• ionotropic, muscarinic

• ligand gated ion channel that has receptor & transducing functions

• nicotinic, ACh Receptors

• AMPA, GABA receptors (contains channels)

• responds to cell impermeant signaling

enzyme - linked receptors

• neurotrophin receptors

• when receptor binds it activates an enzyme (protein kinase → phosphorylates other proteins)

• intracellular

G - protein - coupled receptors

• Ach Receptors

• catocholamine

• dopaminee, norepinephrine, epinephrine

• largest, most diverse

• cell signaling, NTransmission, sensory responses, immune

Intracellular receptors

• inside plasma membrane

• steroid hormones, nitric oxide, thyroid hormone

• receptors are intracellular

• bind to signalling molecule

  • activate receptor

  • cause changes in gene transcription

• bind to DNA upon activation which regulates gene expression

heterotrimeric G-proteins

• when receptor binds to signaling molecule, activates something that causes this to exchange a GDP molecule (inactive) for a GTP molecule

• trimeric G-protein dissociates to 2 components

  • alpha subunit (activated)

  • beta - gamma subunit

• activate target protein

• inactivate spontaneously by interacting w/ GAP

  • dephosphorylate GTP to GDP (turn off)

monomeric G - proteins

• small G proteins, that relay signals from active cell surface receptors to intracellular targets

• dynamin protein

• ras protein

effects on signal transduction pathways

1. Amplification

2. Diversification

3. Elongation of Response Time

neuronal second messengers

• Ca2+

• cyclic AMP

• cyclic GMP

• IP3

• diacylglycerol

• nitric oxide

Ca2+

sources:

• plasma membrane

  • voltage-gated Ca2+ channels

  • various ligand-gated channels

• ER

  • IP3 receptors

  • ryanodinee receptors

Intracellular targets

• calmodulin

• protein kinases

• protein phosphatases

• ion channels

• synaptotagmin

• many other Ca2+ binding proteins

Removal mechanisms

• plasma membrane

  • Na+/Ca2+ exchanger

  • Ca2+ pump

• ER

  • Ca2+ pump

cyclic AMP

Sources

• adenylyl cyclase acts on ATP

Intracellular targets

• protein kinase A

• cyclic nucleotide gated channels

Removal mechanisms

• cAMP phosphodiesterase

IP3

Sources

• phospholipase C acts on PIP2

Intracellular targets

• IP3 receptors on ER

Removal mechanisms

• phosphatases

diacylglycerol

Source

• phospholipase C acts on PIP2

Intracellular targets

• protein kinase C

Removal mechanisms

• various enzymes

regulation of cellular proteins by phosphorylation

• proteins act as molecular switches

  • add phosphate group (protein kinase) to target protein

• to turn on:

  • add phosphate group to protein target

  • 2nd messenger (cAMP or Ca2+) → protein kinase → downstream protein (ion channel, enzyme, protein that regulates gene expression)

• to turn off:

  • protein cleaves phosphate group (dephosphorylates)

  • P group removed → protein to off position

mechanism of activation of protein kinase PKA

PKA

• found in cytoplasm

• when in inactive form

  • regulatory domain is blocking the catalytic domain → can’t phosphorylate proteins

• when 2nd messenger activates them, the regulatory domain separates & allows the catalytic domain to be active

  • catalytic domain is released from regulatory domain & is active

    • catalytic domain phosphorylates target proteins

• regulate: metabolism, gene expression, STP

mechanism of activation of protein kinase CaMKII

• found in cytoplasm

• calcium/calmodulin dependent protein kinase 2

• inactive form: polypeptide is folded up so regulatory domain is blocking catalytic domain

• active form: Ca2+ binds to calmodulin which binds to regulatory domain of protein & linearizes so catalytic domain can be phosphorylated

mechanism of activation of protein kinase PKC

• found in membrane

• requires DAG, Ca2+, PS

• inactive form: regulatory domain is bound to catalytic domain = blocked

• active form: DAG, Ca2+, PS binds to regulatory domain & catalytic domain is released so membrane proteins can be phosphorylated

protein kinases

• add phosphate groups to proteins

• phosphorylate proteins at serine, threonine, & tyrosine residues

• contain catalytic & regulatory domains

• upon activation by appropriate 2ndary messenger, regulatory domain releases catalytic domain for activity

• tyrosine kinases fall into different class of protein kinases

Steps in transcription of DNA to RNA

1. DNA wrapped in chromatin

2. chromatin needs to relax to expose DNA

3. upstream activator site (UAS) is free of proteins & bound by sequence specific transcriptional activator protein (transcription factor)

4. the transcriptional activator protein then binds to co-activator complexes that enable the RNA polymerase w/ its associated factors to bind at the start site of transcription

CREB

a protein activated by cyclic AMP that binds to specific regions of DNA, thereby increasing the transcription rates of nearby genes

• Ca Response Element Binding Protein

• when activated:

  • can bind to specific sequences in DNA molecule on enhancers → allows genes to be transcribed