Signaling

2017-11-03

Conceptual goals

• Understand that cell signaling is done through cascades of interactions and reactions
• Understand the basic mechanism of a G-protein signaling

Skill goals

• Reason about how perturbations to a G-protein signaling cascade would lead to different outcomes

How can you sense your environment and pass on the signal?

Olfactory sensory neurons detect odors in the environment

Human olfactory sensing is amazingly sensitive and flexible

G-protein coupled receptors (GPCRs) are at the heart of olfactory signaling

Each sensory neuron has one type of receptor and can recognize one smell

Steps

• Trigger signal
• Amplify signal
• Pass on signal

Steps

• Trigger signal
• Amplify signal
• Pass on signal

Trigger signal, players:

$GPCR$: G-Protein Coupled Receptor

$G$-protein (three subunits): $G_{\alpha}$, $G_{\beta}$, and $G_{\gamma}$

$GTP$: Guanosine triphosphate

$GDP$: Guanosine diphosphate

$GTP \rightarrow GDP + P_{i}$

guanosine triphosphate

phosphate + guanosine diphosphate

Initial state: $GPCR$ bound to $G \cdot GDP$ complex

Odor molecule binds to $GPCR$, inducing conformational change in $GPCR$ and $G$-protein

$G_{\alpha} \cdot GTP$ has only weak affinity for $GPCR$ so it dissociates

$G_{\alpha}$ slowly catalyzes $GTP \rightarrow GDP + P_{i}$

Meanwhile, the odor molecule diffuses away

Steps

• Trigger signal
• Amplify signal
• Pass on signal

So what does $G_{\alpha} \cdot GTP$ do when it's wild and free in the cell?

$G_{\alpha} \cdot GTP$ allosterically activates adenylate cyclase

Adenylate cyclase starts catalyzing $ATP \rightarrow cAMP + PP_{i}$

$ATP \rightarrow cAMP$

adenosine triphosphate

cyclic adenosine monophosphate

$G_{\alpha} \cdot GTP$ activates adenylate cyclase, which makes a lot of $cAMP$

1 $G_{\alpha}$, many $cAMP$: amplification!

Steps

• Trigger signal
• Amplify signal
• Pass on signal

$cAMP$ binds to a gated $Na^{+}/Ca^{2+}$ channel, which opens and lets $Na^{+}$ rush into the cell

Gated ion channels respond to changes in electrical potential (voltage)

Gated ion channels respond to changes in electrical potential (voltage)

This depolarizes the membrane and kicks off a nerve impulse

Steps

• Trigger signal: $GPCR$ and $G$ protein
• Amplify signal: adenylate cyclase, $cAMP$
• Pass on signal: $Na^{+}/Ca^{2+}$ channel

What would be the effect of a mutation to adenylate cyclase that makes it slower (lowers $V_{max}$)?

Trigger would be normal, less amplification, less transmission

What would be the effect of a mutation to $G_{\alpha}$ that slows its $GTP \rightarrow GDP$ activity (lowers $V_{max}$)?

Trigger would be on longer, more amplification, more transmission

What would be the effect of a mutation to the ion channel that lowered $cAMP$ affinity?

Trigger would be normal, normal amplification, less transmission

Why is it important that $G_{\alpha}$'s $GTP \rightarrow GDP$ activity is slow?

$GTP \rightarrow GDP$ is a timer that makes sure $cAMP$ is made, but not forever

Generality: these sorts of cascades are everywhere

Such pathways construct "logic gates" and "circuits"

Big idea: sensing is usually arranged into cascades

Why might this be?

• Lots of points of regulation
• Small signals can be amplifed
• Makes system only turn on when it's supposed to

Summary

• Cells signal through cascades of interactions/reactions
• For olfactory signaling:
  • Trigger signal: $GPCR$ and $G$ protein
  • Amplify signal: adenylate cyclase, $cAMP$
  • Pass on signal: $Na^{+}/Ca^{2+}$ channel