M04.02.09 G-protein coupled receptors

G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a crucial role in cellular signaling. They are involved in a wide range of physiological processes, including sensory perception, neurotransmission, hormone regulation, and immune response. Here’s a more detailed explanation of G protein-coupled receptors:

Structure: 

GPCRs are integral membrane proteins that span the cell membrane, with an extracellular N-terminus and an intracellular C-terminus. They consist of seven transmembrane helices (TM1-TM7) connected by three intracellular and three extracellular loops. The arrangement of these transmembrane helices creates a ligand-binding pocket on the extracellular side of the receptor.

Ligand Binding and Activation: 

GPCRs are activated by specific ligands, such as hormones, neurotransmitters, or other signaling molecules. When a ligand binds to the receptor, it induces a conformational change in the receptor’s structure. This conformational change leads to the activation of the G protein associated with the receptor.

G Proteins: G proteins are heterotrimeric proteins consisting of three subunits: alpha (α), beta (β), and gamma (γ). When the GPCR is activated, it promotes the exchange of guanosine diphosphate (GDP) bound to the alpha subunit (Gα) with guanosine triphosphate (GTP). This GTP-bound form of Gα dissociates from the βγ subunits and initiates downstream signaling cascades.

Signaling Pathways: 

The activated Gα subunit or the Gβγ dimer can interact with various effector molecules to initiate downstream signaling pathways. The effector molecules include enzymes such as adenylyl cyclase, phospholipase C, and ion channels. These effectors generate intracellular second messengers such as cyclic AMP (cAMP), inositol trisphosphate (IP3), diacylglycerol (DAG), and calcium ions (Ca2+), which mediate further cellular responses.

GPCR Regulation: 

GPCR signaling is tightly regulated to maintain cellular homeostasis. Several mechanisms contribute to the regulation of GPCRs, including:

Desensitization: 

Prolonged or repeated activation of GPCRs leads to desensitization, where the receptor becomes less responsive to the ligand. This can occur through the phosphorylation of the receptor by kinases and the recruitment of arrestin proteins.

Internalization: 

Desensitized GPCRs can be internalized from the cell membrane into intracellular compartments through endocytosis. Internalization can play a role in receptor resensitization or degradation.

Recycling and desensitization: 

Internalized GPCRs can be recycled back to the cell surface after desensitization to regain responsiveness to the ligand.

GPCR Diversity: 

GPCRs exhibit a high degree of diversity in their structure and function. They can be classified into different subfamilies based on their sequence similarity and signaling mechanisms. The different subfamilies have distinct ligand specificities and downstream signaling pathways.

GPCRs are of significant importance in biology and medicine. They are the targets of a large number of drugs, making them one of the most important classes of pharmaceutical targets. Understanding the physiology of GPCRs is crucial for unraveling the mechanisms of cellular signaling and developing therapeutics for various diseases.