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The cAMP-PKA-CREB pathway is crucial in biological processes such as hormone synthesis, metabolism, and memory formation. The statements describe the effects of mutations in this pathway on gene transcription by CREB.

(A)   Loss of function mutation in a cAMP binding site of the PKA regulatory subunit leads to the inactivation of gene expression.

(B)   Activating mutation in the GTP-binding domain of the α subunit of Gs leads to the activation of gene expression.

(C)   Inactivating mutation that prevents the regulatory subunit of PKA from binding the catalytic subunit leads to the activation of gene expression.

(D)   Inactivating mutation in the PKA phosphorylation site of CREB leads to the activation of gene expression.

Which one of the followingstatement is Incorrect?

Correct option is C

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(A) Loss of function mutation in a cAMP binding site of the PKA regulatory subunit leads to the inactivation of gene expression.

• Correct. The regulatory subunit of PKA binds cAMP to activate the catalytic subunit.
• If the cAMP-binding site is mutated (loss of function), PKA remains inactive, preventing CREB phosphorylation, leading to inactivation of gene expression.

(B) Activating mutation in the GTP-binding domain of the α subunit of Gs leads to the activation of gene expression.

• Correct.Gsα (stimulatory G protein) activates adenylyl cyclase, increasing cAMP levels.
• A constitutively active (mutated) Gsα would keep PKA active, continuously phosphorylating CREB and activating gene expression.

(C) Inactivating mutation that prevents the regulatory subunit of PKA from binding the catalytic subunit leads to the activation of gene expression.

• Correct. Normally, the regulatory subunit inhibits PKA by binding to its catalytic subunit.
• If a mutation prevents this binding, the catalytic subunit is always active, leading to constant CREB activation and gene expression.

(D) Inactivating mutation in the PKA phosphorylation site of CREB leads to the activation of gene expression.

• Incorrect. CREB must be phosphorylated by PKA to activate gene transcription.
• If the PKA phosphorylation site on CREB is mutated (inactivated), CREB cannot be activated, leading to loss of gene expression, not activation.

Information Booster:

1. cAMP-PKA Pathway Activation:
• Gsα activates adenylyl cyclase → cAMP production → PKA activation.
• Active PKA phosphorylates CREB, leading to gene transcription activation.
2. PKA Structure and Function:
• PKA has two regulatory subunits and two catalytic subunits.
• cAMP binds the regulatory subunits, releasing active catalytic subunits.
3. CREB Phosphorylation:
• PKA phosphorylates CREB at Ser133, which recruits CBP (CREB-binding protein) to initiate transcription.
• If the phosphorylation site is mutated (D statement), gene activation fails.