Cellular Level
Types of Ligands
Ligands are the signaling molecules the body uses for various cells to communicate with other cells. The adrenal gland can release a hormone such as cortisol, which shares with a large variety of different cells of different organs to have a significant effect, or 1 inhibitory neuron can release a neurotransmitter like γ-aminobutyric acid (GABA) to exert a straightforward impact on another cell. The effect of the ligand is dependent on both the ligand itself and the receptor it targets. For example, small and hydrophobic ligands such as steroids like cortisol often target internal receptors as they can pass through the plasma membrane without help. On the other hand, large or hydrophilic ligands such as GABA cannot pass through the cell membrane and must target cell surface receptors.
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Internal Receptors
These receptors are also known as either intracellular or cytoplasmic. They are found in the cytoplasm of a cell and are often targeted by hydrophobic ligands that can cross the lipid bilayer of the animal plasma cell membrane. Often, these receptors act to modify messenger RNA (mRNA) synthesis and, thus, protein synthesis within the cell. They accomplish this by the ligand-receptor complex traveling to the nucleus and binding DNA at a gene regulatory site, which the receptor and ligand on their own would be unable to do. Testosterone, estrogen, cortisol, and aldosterone are examples of hydrophobic steroid hormones that pass through the plasma membrane to target internal receptors. Internal receptors often work without needing second messengers to relay the signal before mRNA synthesis and protein synthesis are affected, a process unique to internal receptors, as other types work through a cellular cascade that alters protein synthesis.
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Cell-Surface Receptors
These receptors are also known as transmembrane receptors. These proteins are found on the surface of cells and span the plasma membrane. They bind to ligands that cannot pass through the plasma membrane by themselves. These are often hydrophilic ligands or ones too large to make it through. These receptors don’t bind DNA to modify gene transcription and translation but rather perform signal transduction; an extracellular signal triggers an intracellular signal, which usually goes to the nucleus to affect cell functioning. Often, a cell surface receptor is specific for that cell type so that the ligand can only affect the functioning of its target cells. The components of a cell surface receptor can break down into an external ligand-binding domain, a hydrophobic region that spans the membrane, and an intracellular domain that is responsible for starting a second messenger cascade. Cell-surface receptors come in 3 main types: ion channel receptors, GPCRs, and enzyme-linked receptors.
Ion Channel Receptors
When a ligand binds an ion channel receptor, a channel through the plasma membrane opens, allowing specific ions to pass through. This process requires a specialized membrane-spanning region of the receptor. Ligand binding changes the receptor’s shape, allowing specific ions, usually sodium, magnesium, calcium, or hydrogen, to pass. Chemically gated ion channels are on dendrites and the cell bodies of neurons.
GPCRs
GPCRs are a subtype of cell surface receptors that act through a G-protein to start a second messenger cascade, modulating cellular function. The receptor has a ligand-binding site outside the plasma membrane and a transmembrane portion that can bind to a G-protein in the intracellular space. A G-protein is a heterotrimeric protein with 3 subunits: alpha, beta, and gamma. The beta and gamma subunits are attached to the membrane by a lipid anchor. When no ligand is bound to the receptor, the alpha subunit and a guanosine diphosphate (GDP) are bound to the transmembrane receptor and the beta and gamma subunits. When the ligand binds to the receptor, a conformational change activates the G protein, and a guanosine triphosphate (GTP) molecule replaces the GDP molecule on the alpha subunit.
The G-protein dissociates with the beta and gamma subunits remaining attached by their anchor, and the activated alpha subunit, now bound to a GTP molecule, is freed from the intracellular wall of the plasma membrane. Both the beta-gamma dimer and the alpha-GTP can act to propagate the signal cascade. Some common enzymes and second messengers activated by this cascade include adenylate cyclase, cyclic adenosine monophosphate AMP, diacylglycerol, inositol 1, 4, 5-triphosphate, and phospholipase C. GPCRs can be both activating and inhibiting. GPCRs are involved in many functions of the multicellular organism, including but not limited to growth, endocrine signaling, sensation, and clotting.
Enzyme-Linked Receptors
This subtype of transmembrane receptors has a catalytic site on the cytoplasmic domain. When the ligand binds these receptors, they often dimerize, activating the receptor’s catalytic site and resulting in enzymatic activity. There are several types of enzyme-linked receptors; the most common type is the receptor tyrosine kinase. Other examples include receptor serine/threonine kinase, receptor guanylyl cyclase, and receptor tyrosine phosphatases. Receptor tyrosine and receptor serine and threonine kinases dimerize, which causes autophosphorylation to happen at the tyrosine, serine, or threonine sites, respectively. This phosphorylation is what activates the enzymatic activity of the receptor. Many growth signals, such as epidermal and platelet-derived growth factors, work with a receptor tyrosine kinase.
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