The article "The Many Faces of G Protein Signaling" by Heidi E. Hamm provides an in-depth review of the complex mechanisms and diverse roles of G proteins in cellular signaling. G proteins, composed of α, β, and γ subunits, play a crucial role in transducing signals from G protein-coupled receptors (GPCRs) to various intracellular effectors. The article highlights the structural and functional characteristics of G proteins, including their activation by guanine nucleotide exchange and deactivation by GDP hydrolysis. It discusses the recent structural insights into the inactive and active conformations of G proteins, which have provided a framework for understanding their signaling mechanisms. The review also delves into the mechanisms of G protein activation by GPCRs, emphasizing the importance of receptor-specific interactions and the role of specific residues in these interactions. It explores the activation of various effectors by Gα and Gβγ subunits, including adenylyl cyclase, phospholipase C, and potassium channels. The article further examines novel targets of Gα subunits, such as GAIP and nucleobindin, and the diverse effector targets of Gβγ subunits, including potassium and calcium channels, kinases, and Rho family GTPases. The review addresses key questions about the specificity and regulation of G protein signaling, including the determinants of effector interaction, the role of scaffolding proteins, and the mechanisms of cross-regulation. It highlights the importance of molecular interactions in achieving high specificity in vivo and the potential regulatory roles of GTPase-activating proteins and scaffold proteins. Overall, the article underscores the broad range of cellular regulatory activities involving G proteins and the significant implications of these interactions for physiological processes. The rapid progress in structural and mechanistic studies is expected to provide opportunities for altering these interactions in pathological situations.The article "The Many Faces of G Protein Signaling" by Heidi E. Hamm provides an in-depth review of the complex mechanisms and diverse roles of G proteins in cellular signaling. G proteins, composed of α, β, and γ subunits, play a crucial role in transducing signals from G protein-coupled receptors (GPCRs) to various intracellular effectors. The article highlights the structural and functional characteristics of G proteins, including their activation by guanine nucleotide exchange and deactivation by GDP hydrolysis. It discusses the recent structural insights into the inactive and active conformations of G proteins, which have provided a framework for understanding their signaling mechanisms. The review also delves into the mechanisms of G protein activation by GPCRs, emphasizing the importance of receptor-specific interactions and the role of specific residues in these interactions. It explores the activation of various effectors by Gα and Gβγ subunits, including adenylyl cyclase, phospholipase C, and potassium channels. The article further examines novel targets of Gα subunits, such as GAIP and nucleobindin, and the diverse effector targets of Gβγ subunits, including potassium and calcium channels, kinases, and Rho family GTPases. The review addresses key questions about the specificity and regulation of G protein signaling, including the determinants of effector interaction, the role of scaffolding proteins, and the mechanisms of cross-regulation. It highlights the importance of molecular interactions in achieving high specificity in vivo and the potential regulatory roles of GTPase-activating proteins and scaffold proteins. Overall, the article underscores the broad range of cellular regulatory activities involving G proteins and the significant implications of these interactions for physiological processes. The rapid progress in structural and mechanistic studies is expected to provide opportunities for altering these interactions in pathological situations.