The G-protein switch
A GPCR never touches the inside business of the cell directly. When a ligand binds on the outside, the receptor changes shape and grabs a G protein waiting on the inner face of the membrane. That contact flips the G protein from off to on, and the G protein then carries the message onward. The receptor is the doorbell; the G protein is the messenger who actually runs into the house.
There are three flavours of G protein worth knowing by name. The Gs protein (s for stimulatory) turns the signal *up*; the Gi protein (i for inhibitory) turns it *down*; and the Gq protein starts a different relay entirely, based on calcium. The very same neurotransmitter can soothe one tissue and excite another simply because the two tissues couple their receptors to different G proteins.
The relay and its amplification
Once switched on, Gs activates an enzyme in the membrane called adenylyl cyclase, which churns out a small molecule called cyclic AMP. Cyclic AMP is a second messenger — the first messenger was the drug outside, and now this inner molecule carries the news deeper. This handoff from one molecule to the next, each activating the next step, is a signal cascade.
- One drug molecule binds one GPCR on the cell surface.
- That one receptor activates many G proteins before the drug lets go.
- Each Gs activates an adenylyl cyclase, and each cyclase makes many cyclic AMP molecules.
- So one bound drug becomes thousands of inner signals — the cascade has amplified it.
Switching off, and getting tired
A signal that could never be turned off would be a disaster, so the cell has brakes. After a GPCR has been firing for a while, a protein called beta-arrestin clamps onto it, uncouples it from its G protein, and pulls it out of the membrane. The receptor goes quiet even though the drug is still present.
This braking is the molecular root of desensitization: keep a receptor under heavy stimulation and the cell answers less and less. It is a preview of the next guide, where we will see how the cell can also change the *number* of receptors over longer periods.