Cell signaling GPCR

Describe 3 steps of signal transduction

1. Reception - extracellular signal binds to receptor

2. Tranduction - Cascade of intracellular reactions that triggers the cell’s response to the original signal

3. Response - Intracellular signaling proteins alter the activity of effector proteins

List 4 types of intercellular signaling

1. contact-dependent

2. paracrine

3. synaptic

4. endocrine

What is contact-dependent signaling? Give examples

• extracellular signaling molecules remain bound to the surface of the signaling cell and influence only cells that contact it

• not always short-lived; time depends on length of contact

• important during development and in immune responses

What is paracrine signaling? Give examples

• signaling cells secrete signal molecules into the extracellular fluid

• the secreted molecules are often local mediators - act only on neighboring cells

• target cell is usuallly close to signaling cell

• usually fast and short-lived

• subset: autocrine signalling - signaling cell is the target cell

  • Example: cancer cells (signal for survival and proliferation)

What is synaptic signaling? Give examples

• long-range signaling over large distances

• generally fast

• ex: nerve cells (neurons)

  • long branching processes (axons) target cells far away

  • Axons terminate at sites of signal transmission called chemical synapses

  • electrical impulses (action potential) transmitted down the axons

  • neurotransmitter - small signal molecule secreted by presynaptic to postsynaptic cell

What is endocrine signaling? Give examples

• endocrine cells secrete signal molecules called hormones into the bloodstream

• target cell must have specific receptor

• slower due to travel through bood circulation

How do cells respond to signals they receive?

• cells receive many different signals; the decision they make depends on:

  • what kind of receptors they have + the pathway

  • selective receptor expression*

  • differences in intracellular signaling proteins, effector proteins, and activated genes

  • typically a combo of signals promotes a specific response

Define GPCR

• G protein coupled receptors

• largest family of cell surface receptors

  • almost 50% of known drugs work thru GPCRs

• receptor undergoes a conf. change when bound to extracellular signal; allows it to bind to a G protein (GTP-binding protein) — see ntbk

How is cAMP synthesized?

• synthesized from ATP by adenylyl cyclase (aka adenylate cyclase)

• extracellular signal activates a GPCR which is coupled to a stimulatory G protein (Gs)

  • activated alpha subunit of Gs binds and activates adenylyl cyclase

How is cAMP destroyed?

• destroyed by cAMP phosphodiesterase

• exctracellular signal activates a GPCR that activates an inhibitory G protein (Gi)

  • activated alpha subunit of Gi inhibits adenylyl cyclase, reducing cAMP

second messengers

chemicals that are generated in large amounts in response to receptor activation and diffuse away from their source, spreading signal to other parts of the cell

• ex: water soluble IP3, cAMP, and Ca2+; lipid soluble DAG (diacylglycerol)

Describe cholera toxin mechanism

• Gsα is covalently modified (ADP ribosylation) — ADP ribose transfered to α subunit of Gs

  • α subunit can no longer hydrolyze its bound GTP

  • This leads to constant activation of AC (adenylate cyclase) and high levels of cAMP.