29. G-protein coupled receptors (GPCR) consist of three protein subunits  α, β and γ. In unstimulated state, a- subunit is GDP bound and GPCR is inactive. When GPCR gets activated. it acts like guanine nucleotide exchange (GEF) factor and induces a-subunit to release its bound GDP allowing GTP tobind in its place. In order to regulate G-protein activity by regulating GDP/GTP concentration, a subunit acts as
(1) GTPase
(2) GDP kinase
(3) cGMP-specific phosphodiesterase
(4) cAMP-specific phosphodiesterase

G-Protein Alpha Subunit and Its Role as a GTPase in Signal Transduction

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Introduction

Heterotrimeric G-proteins, composed of alpha (α), beta (β), and gamma (γ) subunits, are vital molecular switches in cellular signal transduction. In the resting state, the α-subunit binds GDP and associates with βγ. Activation occurs when a G-protein-coupled receptor (GPCR) acts as a guanine nucleotide exchange factor (GEF), promoting GDP release and GTP binding to the α-subunit. This activates the α-subunit to modulate downstream effectors such as adenylyl cyclase.

The Regulatory Role of the Alpha Subunit

The α-subunit intrinsically possesses GTPase activity, which hydrolyzes bound GTP to GDP, turning itself off and allowing reassociation with βγ, thus terminating the signaling event. This built-in enzymatic activity ensures proper control of signal duration and prevents excessive cellular responses.

• After GTP binding and activation, the α-subunit remains active until its GTPase activity converts GTP back to GDP.

• This hydrolysis reaction is sometimes accelerated by GTPase activating proteins (GAPs), such as RGS proteins, enhancing signal termination.

Why the Other Options Are Incorrect

• GDP kinase: No such kinase regulates GDP concentration in the G-protein cycle.

• cGMP-specific phosphodiesterase and cAMP-specific phosphodiesterase: These enzymes degrade cyclic nucleotides (cGMP and cAMP) and are not involved in regulating GDP/GTP on the α-subunit.

Summary

The G-protein α-subunit acts as a GTPase regulating its activation state by hydrolyzing GTP to GDP. This enzymatic function is crucial for the temporal control of signal transduction downstream of GPCRs.

Correct answer: (1) GTPase