Chemokine Receptors
About Chemokine Receptors
Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. There have been 20 distinct chemokine receptors discovered in humans. Each has a rhodopsin-like 7-transmembrane (7TM) structure and couples to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. Four families of chemokine receptors differ in the spacing of cysteine residues near the N-terminal of the receptor.
Mechanism of Action of Chemokine Receptors
Intracellular signaling by chemokine receptors is dependent on neighboring G-proteins. G-proteins exist as a heterotrimer; they are composed of three distinct subunits. When the molecule GDP is bound to the G-protein subunit, the G-protein is in an inactive state. Following the binding of the chemokine ligand, chemokine receptors associate with G-proteins, allowing the exchange of GDP for another molecule called GTP, and the dissociation of the different G protein subunits. The subunit called Gα activates an enzyme known as Phospholipase C (PLC) that is associated with the cell membrane. PLC cleaves Phosphatidylinositol (4,5)-bisphosphate (PIP2) to form two second messenger molecules called inositol triphosphate (IP3) and diacylglycerol (DAG); DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades, affecting a cellular response.
- Chemotaxis: Chemokine receptors initiate signaling by binding to their specific chemokines. These chemokines are a class of small-molecule cytokines that can play important roles in inflammation, immune response, and cell migration.
- G-protein Coupling: When chemokines bind to chemokine receptors, the chemokine receptors undergo a conformational change that activates intracellular G-proteins.
- G protein Signaling: Activated G proteins can generate cellular responses through two major signaling pathways: the Gα subunit and the Gβγ subunit. Activated Gα subunits can regulate the production of intracellular second messengers, such as cyclic adenosine monophosphate (cAMP) and phosphatidylinositol (PI) signaling pathways. Activated Gβγ subunits activate protein kinases such as protein kinase C (PKC) and phospholipase C (PLC).
- Downstream Signaling: The activated G protein signaling pathway ultimately leads to a series of downstream reactions within the cell, such as cell migration (chemotaxis), cell adhesion, cell proliferation, and cell differentiation. These responses are achieved by activating specific protein kinases, regulating gene expression, and altering cytoskeletal structure.
Fig.2 Chemokine receptors and their ligands. (Proudfoot AE, et al., 2002)
Chemokines are divided into subclasses on the basis of the spacing of the N-terminal cysteine residues. The receptors for the α (or CXC) subclass are shown in blue, the receptors for the β (or CC) subclass in red and the receptors for the minor subclasses (C and CX3C) in green. The pairing of chemokines to their receptors has been carried out mainly by receptor-binding assays.
Functions of Chemokine Receptors
Chemokine receptors coordinate a variety of biological functions, including:
- Cell migration and Homing
Chemokine receptors play a crucial role in directing immune cells to specific tissues during immune surveillance and inflammation. They regulate the directed migration (chemotaxis) of immune cells (including leukocytes, lymphocytes, monocytes, and others) to sites of infection, injury, or inflammation.
- Immune Cell Activation
Chemokine receptors control the activation and regulation of immune cells such as T-cells, B-cells, and natural killer (NK) cells. They contribute to immune cell activation, antigen presentation, and the formation of immune synapses.
- Inflammation and Tissue Repair
Chemokine receptors regulate the recruitment and activation of immune cells during inflammation, contributing to the reduction of inflammation and tissue repair processes.
- Cancer Metastasis
Abnormal chemokine receptor expression and function promote migration and invasion of cancer cells, leading to cancer development and metastasis.
Fig.3 Functions of chemokines and their receptors. (Hughes CE, et al., 2018)
Available Resources for Chemokine Receptors
Chemokine receptors serve a variety of functions including, but not limited to, regulating migration and directional navigation of immune cells, mediating inflammatory responses, participating in organ development and maintenance, and playing a role in pathophysiological processes in cancer and autoimmune diseases. By modulating the activity and selectivity of chemokine receptors, researchers can explore novel therapeutic strategies in areas such as immunomodulation, anti-inflammation, and tumor therapy. Creative BioMart offers a wide range of products and services for chemokine receptor research, providing researchers with a valuable resource for studying the mechanism of action and function of these receptors. The following chemokine receptors are displayed, click to view all related molecules/targets and research reagents. Please feel free to contact us with any questions or requests.
References:
- Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol. 2002;2(2):106-115.
- Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944-2971. doi:10.1111/febs.14466.
