G Protein Coupled Receptors: Videos & Practice Problems

G Protein Coupled Receptors (GPCRs) represent the largest family of cell surface receptors, with over 700 types identified in humans. These receptors are integral to cellular signaling, primarily functioning through interactions with G proteins. The structure of GPCRs is characterized by a single polypeptide chain that traverses the cell membrane seven times, creating three extracellular loops and three intracellular loops. The extracellular loops are responsible for ligand binding, while the intracellular loops interact with signaling proteins.

At the cytosolic side, GPCRs are associated with trimeric G proteins, which act as molecular switches. These G proteins are activated when bound to guanosine triphosphate (GTP) and inactivated when bound to guanosine diphosphate (GDP). This mechanism is crucial in cell biology, where activation typically occurs in the presence of GTP, while GDP binding leads to inactivation. Once activated, G proteins can relay signals to various downstream effectors, facilitating a wide range of cellular responses.

The activation process begins when a signaling molecule, such as a hormone, binds to the GPCR, inducing a conformational change in the receptor. This change prompts the G protein to switch from GDP to GTP, thereby activating it. The regulation of GPCR signaling is essential for maintaining cellular homeostasis and involves controlling the activity of G proteins. Factors that influence GTP hydrolysis play a significant role in this regulation; rapid hydrolysis leads to brief activation, while slower hydrolysis prolongs the active state.

Desensitization is a key regulatory mechanism that prevents active receptors from continuously activating G proteins. One example of this is the G Protein Coupled Receptor Kinase 2 (GRK2), which competes with G proteins for binding to GPCRs. When GRK2 binds to a GPCR, it prevents G protein activation, effectively silencing the receptor's signaling capability despite the presence of the ligand. Other regulatory mechanisms include receptor inactivation, sequestration (where receptors are confined to a specific area, reducing their responsiveness), and downregulation (decreasing the number of receptors on the cell surface).

Understanding the structure and signaling pathways of GPCRs is vital for comprehending their role in various physiological processes and their implications in pharmacology and disease treatment.

G protein-coupled receptors (GPCRs) play a crucial role in various signaling pathways within cells, with three primary pathways being particularly significant: cyclic AMP (cAMP) signaling, calcium signaling, and inositol phospholipid signaling.

The cAMP pathway is a universal signaling mechanism found in nearly all studied cells. cAMP acts as a second messenger, typically maintained at low levels within the cell. When extracellular signals activate GPCRs, they trigger G proteins that can either stimulate or inhibit the enzyme adenylate cyclase. This enzyme is responsible for synthesizing cAMP from ATP. An increase in cAMP concentration leads to various cellular responses, while phosphodiesterase degrades cAMP, thus regulating its levels. Understanding the roles of cAMP and adenylate cyclase is essential for grasping this pathway.

Calcium ions also serve as vital signaling molecules, with their intracellular concentration kept low under resting conditions. GPCR activation can lead to an increase in cytosolic calcium levels, which is critical for the function of various proteins and enzymes. One key player in calcium signaling is calmodulin, a protein that mediates cellular responses to calcium. When calcium levels rise, calmodulin undergoes a conformational change, allowing it to interact with and regulate numerous target proteins, including CaM kinases that influence gene transcription.

The inositol phospholipid signaling pathway involves a specific G protein known as Gq. Upon activation, Gq stimulates phospholipase C, which cleaves a membrane lipid called PIP2 into two important second messengers: inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 travels to the endoplasmic reticulum (ER), where it binds to receptors that open calcium channels, facilitating further calcium influx into the cytosol. Meanwhile, DAG remains in the membrane and activates various signaling pathways, including those involving calmodulin. This pathway exemplifies the interconnectedness of signaling mechanisms, as the effects of calcium signaling can influence multiple cellular processes simultaneously.

In summary, these three GPCR-mediated pathways—cAMP signaling, calcium signaling, and inositol phospholipid signaling—demonstrate the complexity and interrelated nature of cellular signaling. Understanding these pathways is essential for comprehending how cells respond to external stimuli and regulate various physiological processes.