Describe the downstream signalling of GPCRs

G-protein-coupled receptors (GPCRs) are transmembrane receptors that help the cell to receive signals from the external environment and pass them inside the cell. These signals can be in the form of hormones, neurotransmitters and sensory stimuli like smell or light. When a signal binds to the receptor, it activates the intracellular machinery to start a process known as downstream signalling. This signalling starts after the receptor is activated and ends when the final cellular response begins.

There are five main steps in the downstream signalling of GPCRs, starting from ligand binding and ending with kinase activation.

Step 1: Ligand Binding and GPCR Activation

The first step begins when an external ligand like epinephrine or serotonin binds to the extracellular part of the GPCR. This binding causes a conformational change in the structure of the receptor. Because of this shape change, the cytoplasmic portion of the GPCR becomes able to interact with the nearby heterotrimeric G-protein present inside the cell membrane.

This structural change in GPCR prepares it to activate the G-protein, which is the next step.

Step 2: G-protein Activation

The heterotrimeric G-protein is made of three subunits: α (alpha), β (beta) and γ (gamma). In its inactive state, GDP is bound to the α-subunit. When the activated GPCR comes in contact with the G-protein, it causes the GDP to be exchanged for GTP. This process activates the G-protein. As a result, the α-subunit separates from the βγ dimer. Now both these parts become active and start moving inside the membrane.

In the next step, these activated G-protein subunits will pass the signal forward to target enzymes.

Step 3: Activation of Effector Enzymes

Once the G-protein is activated, the α-subunit or the βγ dimer binds to effector proteins such as:
  • Adenylyl cyclase (activated by Gsα and inhibited by Giα), which converts ATP to cyclic AMP (cAMP)
  • Phospholipase C (PLC) (activated by Gqα), which cleaves PIP₂ into IP₃ and DAG
  • Ion channels, such as K⁺ or Ca²⁺ channels, which are regulated by βγ dimers
These enzymes do not directly cause the final response but produce small signalling molecules called second messengers, which spread the signal inside the cytoplasm.

The next step will explain how these second messengers are generated.

Step 4: Second Messenger Production

The effector enzymes now convert existing molecules into second messengers:
  • Adenylyl cyclase converts ATP into cAMP
  • Phospholipase C breaks PIP₂ into IP₃ and DAG
  • IP₃ causes the release of Ca²⁺ ions from the endoplasmic reticulum
These small second messengers quickly move inside the cytoplasm and amplify the signal by spreading it to different regions of the cell.

These messengers now activate special kinases, which is the final step.

Step 5: Kinase Activation and Signal Amplification

The second messengers activate different protein kinases such as:
  • Protein kinase A (PKA), activated by cAMP
  • Protein kinase C (PKC), activated by DAG and Ca²⁺
  • Ca²⁺/Calmodulin-dependent kinase (CaMK), activated by Ca²⁺
These kinases phosphorylate specific target proteins inside the cell. This causes changes in gene expression, metabolic activity, ion channel opening and other functional responses.

This marks the end of downstream signalling, as the signal is now converted into an actual cellular response.





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