Your assistant Igor is studying a neurotransmitter-stimulated GPCR pathway, hypo

Question

Your assistant Igor is studying a neurotransmitter-stimulated GPCR pathway, hypothesized to stimulate the expression of genes that increase retention of memory. He plans to test his hypothesis using a cell line expressing this GPCR. If his hypothesis is correct, what would be the expected outcome on memory gene expression? Explain you reasoning for each answer. d. a mutation in the nuclear import sequence of PKA from PPKKKRKV to PPAAAAAV e. deletion of a functional phosphatase for the gene regulatory protein

Explanation / Answer

G-protein coupled receptors (GPCR) are a large family of proteins that contain seven transmembrane domains. The extracellular N-terminal and exoloops create the interface for agonist interactions. The cytoplasmic C-terminal and cytoloops determine the binding to specific heterotrimeric G-proteins composed of alpha, beta and gamma subunits. GPCRs can associate into dimers and oligomers which enhances sensitivity and specificity of response. There are multiple genes for G-protein alpha, beta and gamma subunits leading to thousands of possible alpha:beta:gamma combinations. Both the Galpha and the Gbetagamma subunits have signaling roles. G-protein Galpha subunits bind GDP/GTP. Galpha subunits belong to subfamilies such as Galphas; Galphai; Galphaq and Galpha12. Each subfamily has gene variants. Galphas (Gas) subunits are associated most often with the activation of adenylyl cyclase and/or calcium ion channels whereas the Galphai (Gai) subunits are typically adenylyl cyclase and calcium ion channel inhibitors. Galphaq (Gaq) family variants; aq, a11, a14, a15, a16 are generally associated with the activation of phospholipase C. Galpha12/13 subunits have been linked to the activation of specific Rho guanine nucleotide exchange factors (RhoGEF); LARG, p115 and PDZ. These GEFs activate the Rho/Rock pathway which is linked to cell proliferation, differentiation, migration and survival. Galpha12/13 is also linked to the induction of apoptosis via activation of JNK through two separate pathways involving ASK1 or MEKK-1 which are MAP3Ks. Gbetagamma (Gbg) dimers also have critical roles in the regulation of GPCR linked effectors. Gbetagamma subunits mediate formation of Shc-Src complexes leading to activation of the Ras-Raf1-MEK-ERK pathway. They also affect PI3Kgamma, protein kinase D (PKD), calcium and potassium channels, adenylyl cyclase 2 (AC-2), phospholipase C-beta2 (PLCbeta2), and beta-adrenergic receptor kinase (betaARKinase) activation. e. deletion of a functional phosphatase for the gene regulatory protein

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