G protein couple receptors

Second Messengers Involved in GPCRs

Earlier we have discussed the basics of signal transduction, G-protein coupled receptor(GPCR) and its basic signaling pathway. Now we’ll discuss the Targets of G-proteins / Second Messenger Systems involved in it.

Most important 5 key factors in receptor mechanism:

Second messengers are the molecules that convey the signals received on the cell surface via receptor to target molecules in the cytoplasm or in the nucleus. They also play a major role in the amplification of the signals.

cAMP Pathway:

1. cAMP (cyclic 3,5- adenosine monophosphate) is a nucleotide synthesized in the cell by the membrane-bound enzyme Adenylyl Cyclase (AC).
2. Adenylyl cyclase catalyzes the cyclization of ATP→ cAMP by cleaving pyrophosphate (PPi).
3. AC is activated by G_sα subunit and inhibited by the G_iα subunit. Thus, modulation of the catalytic activity of AC controls the increase or decrease in the concentration of cAMP in the cell.

PKA:

• cAMP activates the enzyme Phosphokinase A (Note: always remember kinases bring about phosphorylation).
• PKA has 2 catalytic subunits reversibly bound with a regulatory subunit. 
• 4 cAMP molecules bind with R2C2 complex and thus by conformational changes the affinity of the regulatory subunit(R) towards catalytic subunits(C) is weakened.
• The activated catalytic subunits then phosphorylate cAMP response element-binding protein (CREB) which is present in the nucleus.
• CREB binds to the cAMP response element (CRE) of the promoter site of its target genes and thus gene transcription occurs.

PDEs:

• It is a family of 24 types of signaling proteins that are regulated via gene transcription, cyclic nucleotides, β arrestins, PKs, etc.
• Phosphodiesterases (PDEs) hydrolyze the 3,5- phosphodiester bond in cAMP and cGMP thus stops their action.
• PDEs are drug targets for several disorders i.e., asthma, atherosclerosis, heart failure, erectile dysfunction, COPD, etc.

G_q-PLC-DAG/ IP₃-Ca²⁺ Pathway:

1. The Phospholipase C pathway is activated by G_qα subunit and inhibited by G_iα subunit.
2. As the name suggests, PLC hydrolyzes phospholipids – Phosphatidylinositol-4,5,-bisphosphate (PIP₂) and thereby producing 2 products – Inositol-1,4,5-triphosphate (IP₃) and Diacylglycerol(DAG).
3. IP₃ is hydrophilic in nature that’s why it diffuses in the cytoplasm and binds with the receptors of endoplasmic reticulum causing the release of Intracellular Ca²⁺ stores in the cytoplasm.
4. The increase in Ca²⁺ in the cytoplasm activates many physiological functions – muscle contraction, hormone secretion, synaptic transmission, apoptosis etc.
5. DAG activates PKC that phosphorylates other proteins and produce cellular effects.

G_q-PLC-DAG/ IP₃-Ca²⁺ Pathway

The role of cGMP Pathway as a second messenger system and the rest of the topics related to GPCR will be discussed in the upcoming blogs. Till then stay tuned and subscribe so that you don’t miss any updates.

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