Cell surface receptor

Membrane receptors are specialized protein molecules in the membranes of cells, to which extracellular signal molecules (usually hormones or cell recognition molecules) attach, triggering changes in the function of the cell. This process is called signal transduction: the external signal is transduced into intracellular action. They are hundreds of receptors are known and there are undoubtedly many more yet to be discovered.

Almost all known membrane receptors are proteins. They can be various kinds of proteins such as glucoprotein, lipoprotein, glycolipidprotein etc. A certain cell membrane can have several membrane receptors with various amounts on its surface. A certain receptor may also have different concentrations on different membrane surfaces, depending on the membrane and cell function. The receptors usually form “clusters” on the membrane surface, therefore the distribution of receptors on membrane surface is mostly heterogeneous.

Signal transduction process through membrane receptors involve the External Reactions in which the ligand binds to a membrane receptor and the Internal Reactions in which intracellular response is triggered.

Signal transduction through membrane receptors usually requires 4 characters: 1. Extracellular signal molecule: an extracellular signal molecule is produced by one cell and is capable of traveling to neighboring cells, or to cells that may be far away. 2. Receptor protein: the cells in an organism must have cell surface receptor proteins that bind to the signal molecule and communicate its presence inward into the cell. 3. Intracellular signaling proteins: these distribute the signal to the appropriate parts of the cell. The binding of the signal molecule to the receptor protein will activate intracellular signaling proteins that initiate a signaling cascade (a series of intracellular signaling molecules that act sequentially). 4. Target proteins: the conformations or other properties of the target proteins are altered when a signaling pathway is active and changes the behavior of the cell.

The membrane receptors are mainly divided into 3 classes: The ion-channel-linked receptors; The G-protein-linked receptor and 3. enzyme-linked receptor.

Ion-channel-linked receptors: These receptors are ion-channels (including cation-channels and anion-channels) themselves and constitute a large family of multipass transmembrane proteins. They are involved in rapid signaling events most generally found in excitable cells such as neurons and are also called ligand-gated channels.

In the signal transduction event in a neuron, the neurotransmitter binds with the receptor and alters the conformation of the protein, which opens the ion-channel, allowing extracellular ions go into the cell. The ion permeability of the plasma membrane is altered, and this will instantaneously convert the extracellular chemical signal into intracellular electric signal, which will alter the excitability of the cell.

Acetylcholine receptor is a kind of cation-channel linked receptor. The protein consists of 4 subunits: α, β, γ, and δ subunits. There are two α subunits, containing one acetylcholine binding site each. This receptor can exist in three different conformations. The unoccupied-closed state is the protein at its original conformation. After two molecules of acetylcholine bind simultaneously to the binding sites on α subunits, the conformation of the receptor is altered and the gate is opened, allowing for the penetration of many ions and small molecules. However, this occupied-open state can only last for a very short period of time and then the gate is closed again, forming the occupied-closed state. The two molecules of acetylcholine will quickly dissociate from the receptor and the receptor will returns to its unoccupied-closed state and is ready for next transduction cycle again.

Enzyme-linked receptors: These receptors are either enzymes themselves, or are directly associated with the enzymes that they activate. These are usually single-pass transmembrane receptors, with the enzymatic portion of the receptor being intracellular. The majority of enzyme-lined receptors are protein kinases, or associate with protein kinases.

Currently there are 6 known types of enzyme-linked receptors: Receptor tyrosine kinases; Tyrosine kinases associated receptors; Receptor-like tyrosine phosphatases; Receptor serine/threonine kinases; Receptor Guanylyl cyclases and Histidine kinase associated receptors. Receptor tyrosine kinases is the one kind with the largest population and most widely application. The majority of these molecules are receptors for growth factors and hormones like epidermal growth factor (EGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor(HGF), insulin, nerve growth factor (NGF) etc.

Most of these receptors will dimerize after binding with their ligands in order to activate further signal transductions. For example, after the epidermal growth factor (EGF) receptor binds with its ligand EGF, two receptors dimerize and then undergo phosphorylation of the tyrosine residues in the enzyme portion of each receptor molecule, which will activate the tyrosine protein kinease and analyze further intracellular reactions.

G-protein-linked receptors: These are receptors that, upon ligand binding, activate a G protein. G-protein is a trimeric GTP-binding regulatory protein which has 3 subunits: α、β and γ.

The α subunit can bind with GDP. The binding of the ligand to the receptor would cause the phosphorylation of GDP and activate the α subunit, which will then dissociate with β and γ subunits. The activated α subunit of G protein can further affect other intracellular signaling proteins, or target proteins directly.

There are two principle signal transduction pathways involving the G-protein linked receptors: cAMP signal pathway and Phosphatidylinositol signal pathway.

cAMP signal pathway The cAMP signal transduction contains 5 main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri)；Stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi)；Adenylyl cyclase; Protein Kinase A (PKA); and cAMP phosphodiesterase.

Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone (Ri) is a receptor that can bind with inhibitory signal molecules.

Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs) and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is a linked to an inhibitory hormone receptor and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.

The Adenylyl cyclase is a 12 transmembrane glucoprotein that catalyzes ATP to form cAMP with the help of cofactor Mg2+or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator to Protein kinase A.

Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzyme in matabolic pathway and it can also regulate specific gene expression, cellular secretion and membrane permeability. The protein enzyme contains two catalytic subunits and two regulative subunits. When there is no cAMP，the complex is inactive. After cAMP binds with the regulative subunits, it alters the conformation of these subunits, causing the dissociation of the regulative subunits, which activate protein kinase A and allow for further biological effects.

cAMP phosphodiesterase is an enzyme that can degrade cAMP to 5’-AMP, which will terminate the signal.

Phosphatidylinositol signal pathway In phosphatidylinositol signal pathway the extracellular signal molecule binds with the G-protein receptor on cell surface and active phospholipase C which is located on the plasma membrane. The lipase hydrolyzes phosphatidyl inositol 4,5- biphosphate (PIP2) into two second messegers: Inositol 1,4,5-triphosphate (IP3) and Diacylglycerol (DAG). IP3 binds with the receptor in the membrane of the smooth endoplasmic reticulum and mitochondria, help open the Ca2+ channel and DAG will help activate Protein Kinase C, which will cause series of biological effects. DAG will help activate Protein Kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses. The effects of Ca2+ is also remarkable: it cooperates with DAG in activating PKC and can activate CaM kinase pathway, in which calcium modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in cAMP signal pathway.