69. The extracellular domain of a cell surface receptor (A) was switched with the extracellular domain of another receptor (B) to create a chimeric receptor (B-A). Assuming that there is no effect on the functionality of the domains in the chimeric receptor, what is the most likely outcome in the presence of the ligand for receptor B?
(1) The ligand will activate the pathway normally triggered by receptor A.
(2) The ligand will activate the pathway normally triggered by receptor B.
(3) The chimeric receptor will fail to transduce any signal in response to the ligand.
(4) The chimeric receptor will cause constitutive activation of the signalling pathway.

Understanding the Chimeric Receptor (B-A)

When the extracellular domain of receptor B is fused to the transmembrane and intracellular domains of receptor A, the resulting chimeric receptor (B-A):

• Will bind the ligand specific to receptor B due to the presence of receptor B’s extracellular domain.

• Will transduce the signal via receptor A’s intracellular signaling machinery, because the intracellular domain remains that of receptor A.

This means the ligand for receptor B can activate the signaling pathway normally triggered by receptor A, assuming domain functionality is preserved.

Explanation of Answer Choices

1. The ligand will activate the pathway normally triggered by receptor A.
   This is the expected outcome. The extracellular domain dictates ligand specificity, so ligand B binds the chimeric receptor, but the intracellular domain of receptor A controls which pathway is activated.

2. The ligand will activate the pathway normally triggered by receptor B.
   This is incorrect. Although the ligand binds receptor B’s extracellular domain, signaling depends on the intracellular domain, which is from receptor A.

3. The chimeric receptor will fail to transduce any signal in response to the ligand.
   This would only be true if domains were nonfunctional or incompatible, but the question states no such effect.

4. The chimeric receptor will cause constitutive activation of the signalling pathway.
   Constitutive activation implies constant signaling without ligand, which is not implied by the domain swap.

Correct Choice

(1) The ligand will activate the pathway normally triggered by receptor A.

Additional Context: Chimeric Antigen Receptors (CARs)

Chimeric receptors combining ligand-binding and signaling domains are widely used in immunotherapy (e.g., CAR-T cells), illustrating that ligand specificity and signaling responses can be modular and interchangeable, much like in this scenario.