G protein-coupled receptors GPCRs are a large family of cell surface receptors that play a crucial role in signal transduction pathways in cells. They are involved in various physiological processes, such as sensory perception, immune response, and hormone regulation. GPCRs are activated by a diverse range of ligands, including neurotransmitters, hormones, and sensory stimuli.Initiation of signal transduction pathways by GPCRs:1. Ligand binding: The process begins when an extracellular ligand e.g., a hormone or neurotransmitter binds to the GPCR. This binding event occurs at the receptor's extracellular domain, which is specific to the ligand.2. Conformational change: Ligand binding induces a conformational change in the GPCR structure, which is transmitted through the transmembrane helices to the intracellular domain of the receptor.3. G protein activation: The intracellular domain of the activated GPCR interacts with a heterotrimeric G protein, which consists of three subunits: , , and . This interaction causes the exchange of GDP guanosine diphosphate for GTP guanosine triphosphate on the subunit, leading to the dissociation of the G protein into two parts: the G-GTP complex and the G dimer.4. Effector activation: The dissociated G-GTP and G subunits can then interact with various downstream effector molecules, such as adenylyl cyclase, phospholipase C, or ion channels. This interaction activates the effectors, leading to the production of second messengers e.g., cAMP, IP3, or Ca2+ , which in turn initiate various intracellular signaling cascades that ultimately modulate cellular functions.Modulation of GPCR activity by allosteric ligands:Allosteric ligands are molecules that bind to a site on the GPCR distinct from the orthosteric ligand-binding site. These ligands can modulate the receptor's activity by either enhancing or inhibiting its response to the orthosteric ligand. There are two main types of allosteric ligands:1. Positive allosteric modulators PAMs : These ligands enhance the receptor's response to the orthosteric ligand, either by increasing the ligand's binding affinity or by enhancing the receptor's efficacy i.e., the ability to activate the G protein . PAMs can be used to amplify the cellular response to endogenous ligands, which may be beneficial in conditions where the ligand concentration is low or the receptor's sensitivity is reduced.2. Negative allosteric modulators NAMs : These ligands inhibit the receptor's response to the orthosteric ligand, either by decreasing the ligand's binding affinity or by reducing the receptor's efficacy. NAMs can be used to dampen the cellular response to endogenous ligands, which may be beneficial in conditions where the ligand concentration is high or the receptor's sensitivity is increased.In summary, GPCRs initiate signal transduction pathways in cells by undergoing a conformational change upon ligand binding, which leads to the activation of G proteins and downstream effector molecules. The activity of GPCRs can be modulated by allosteric ligands, which can either enhance or inhibit the receptor's response to the orthosteric ligand, providing a means to fine-tune cellular signaling processes.