G–protein coupled receptors (GPCRs)
G-protein coupled receptors (GPCRs), also known as seven-transmembrane receptors, are a significant family of cell receptors that help cells respond to external stimuli, such as light and chemical signals. Found in all eukaryotic organisms, including humans, animals, plants, fungi, and protozoa, GPCRs play a vital role in many biological processes. These receptors consist of a single polypeptide that forms seven spiral segments embedded in the cell membrane, allowing them to interact with G proteins upon the binding of external signaling molecules, or ligands. This interaction triggers a cascade of biochemical events within the cell, leading to various physiological responses.
The importance of GPCRs in medicine is underscored by their role in developing treatments for a wide range of diseases, such as cancer, diabetes, and schizophrenia. Approximately 30 to 50 percent of clinical drugs target only a small subset of GPCRs, highlighting their therapeutic potential. Additionally, researchers are interested in orphan GPCRs—those with unknown functions and ligands—believing that understanding these receptors could lead to novel drug discoveries. Overall, GPCRs are crucial for maintaining health and understanding their signaling pathways may provide insights into better disease management.
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G–protein coupled receptors (GPCRs)
G-protein coupled receptors (GPCRs), which may be alternately called seven-transmembrane receptors (or 7TM receptors), are a family of diverse cell receptors that are responsible for processing cell responses to external stimuli. Cell receptors are molecules composed of proteins that receive and process signals from outside a cell. They allow cells to determine how to react to such environmental factors as light, odors, nutrients, and information from other cells. These receptors are found in all eukaryotes, a taxonomic domain of life that includes all living organisms with both nuclei and organelles found within cell membranes. GPCRs are therefore found in such diverse forms of life as humans, animals, plants, fungi, and protozoa.
The study of GPCRs is regarded as particularly valuable due to the number of pharmaceutical drugs that have been developed to specifically interact with this family of cell receptors and treat many types of diseases. Doctors use binding agents that work with GPCRs to manage such illnesses as allergic rhinitis, cancer, chronic pain, diabetes, hypertension, and schizophrenia. These medications are designed to bind with specific types of GPCRs located on cell surfaces to elicit a specific positive bodily response.
Background
The structures of GPCRs have remained static over the course of eukaryotic evolution. As a result, despite the vast differences between eukaryotes, GPCRs have retained a common structural form. GPCRs consist of single polypeptide (a type of molecule made of amino acid chains). This polypeptide is wrapped into a circular shape that is itself twisted into seven spiral segments that are interlaced throughout the cell's plasma membrane. The end loops from these segments are found both inside and outside the cell. This crisscrossing of the cell membrane allows the GPCRs to receive and transmit signals. The loops outside the cell form nets where the extracellular molecules bind to GPCRs. The intracellular portion is called the C-terminus, while the outside extracellular part is the N-terminus.
As their name suggests, GPCRs interact exclusively with associated G proteins (guanine nucleotide-binding proteins). When a ligand (a type of external signaling molecule) bonds with a GPCR, it changes the structure of the GPCR. This structural change signals the start of a biochemical interaction between the GPCR and G protein. This reaction causes enzymes to produce second messengers. Second messengers are tiny molecules that are responsible for the operation and coordination of the intracellular signal pathways. These second messengers allow the cells to form responses to environmental stimuli such as light, hormones, and nerve transmissions. When the G proteins are bonded to a nucleotide called guanosine triphosphate (GTP), they transmit biological signals (or, move to the "on" position). When they are bonded to guanosine diphosphate (GDP), they are dormant (in the "off" position).
Many classes of cell surface receptors exist. The GPCR family of receptors represents the largest of these, and they are in charge of many important biological functions. The functional complexity and number of GPCRs depends on the host organism. Complex multicellular organisms have a greater array of GPCRs than simpler, single-celled eukaryotic organisms such as yeast. In humans, GPCRs have been identified in the regulation of moods, balance of water in the body (homeostasis), energy levels, and the senses of taste, sight, and smell.
GPCRs that act in an abnormal manner have been linked to the growth, metastasis, and spread of some forms of cancer. Cancer stem cells (CSCs) are able to transform normal stem cells into copies of themselves in part by seizing control of the signaling pathways operated by GPCRs and thus the mechanisms used to control healthy stem cells. One such method of hijacking these regulatory processes is to appropriate the ability of healthy stem cells to self-renew. This allows CSCs to regenerate tumors even after a successful cancer treatment. In such cases, even after a patient goes into remission from cancer, CSCs may develop resistance to treatments. CSCs have also been shown to hijack the signals of GPCRs to avoid detection by the immune system, to promote the growth of tumors by increasing their blood supply, and to push CSCs into neighboring tissues and organs. Scientists believe if they can learn how the signaling pathways operated by GPCRs are different in patients with cancerous versus healthy stem cells, they may be able to develop new methods of cancer treatment.
Scientists traditionally identify three families of GPCRs: type A, which consist of rhodopsin-like receptors (which transmit signal interactions with guanine nucleotide binding proteins); type B, the secretin-glucagon receptors (which are regulated by peptide hormones); and type C, which incorporates all metabotropic glutamate receptors (which bind with glutamate).
GPCR Drug Applications
Approximately one thousand GPCRs are known. However, between 30 and 50 percent of drugs regularly used in clinical treatments are designed to interact with only thirty of these receptors. Many of the functions of the remaining GPCRs and the ligands that they interact with remain unknown. These GPCRs with undetermined ligands are called orphan GPCRs (oGPCRs). Researchers believe that discovering the functions of oGPCRs and creating drugs that target them may have vast potential for future research.
The exact methods drugs bind to GPCRs are not completely understood, in part because it requires studying an unstable structural state that occurs only briefly. However, drugs can work to either create or block GPCR bonding, depending on the desired result. Clozapine, for instance, blocks the binding of GPCRs with dopamine or serotonin, a set of receptors that are associated with heightened levels of schizophrenia. Blocking these receptors can reduce the symptoms of this disease.
Another type of GPCR regulates hormone secretions in the pancreas. Diabetes mellitus (or just diabetes) is an illness in which the body has episodes where it produces high levels of blood sugars called glucose—a condition called hyperglycemia. Hyperglycemia occurs when the body has reduced or nonexistent levels of insulin secretion (type 1 DM) or fails to respond to the signals provided by insulin (type 2 DM). As with insulin, secretion levels of another hormone called glucagon may be abnormal. Insulin and glucagon are made by a collection of specialized cells called the islets of Langerhans. A key form of intracellular communication involved in regulating these hormones occurs through GPCRs. As a result, GPCRs are a major focus of diabetes research and treatments. Studies have sought to determine how GPCRs behave differently in normally functioning pancreases and those in patients with diabetes. Medical researchers believe that using medications that correct the messaging of GPCRs will improve the health of diabetes patients.
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