Receptors

Receptors (from lat. recipere = to take up or receive) belong on a molecular level to a family of cellular proteins or protein complexes whose task it is to mediate the effects of the body's own signal substances. Such receptors are also used, for example, by pharmaceuticals, which can act agonistically, i.e. activating receptors, or antagonistically, inhibiting receptors.

In principle, receptors have 2 functions:

• Binding of the signalling substance generally according to a lock-and-key principle
• Initiation of signals that stimulate or inhibit cellular functions.

Receptors protrude from the surface of a biomembrane, if membrane-bound (membrane-bound receptors), or they are positioned inside the cell (intracellular receptors). After their activation, they trigger specific signalling processes.

Thus, a distinction is made at the molecular level:

• membrane-bound receptors
• and
• intracellular receptors (steroid receptors, receptors for vitamin D, thyroid hormones, retinoid receptors)

Membrane recept ors: Membrane receptors are located on the surface of biomembranes (e.g. on cell membranes or on membranes of cell organelles). They consist of proteins, which often have further modifications (e.g. carbohydrate chains). Membrane receptors have a specific fit for small molecules (ligands), or also for parts of larger molecules, which dock to a specific receptor structure according to the lock-and-key principle. Membrane receptors are used for cell adhesion and/or signal transduction or also for the import of substances into the cell. Membrane receptors are also used as docking stations by viruses in order to penetrate a host cell.

The following membrane receptors can be distinguished (see figure):

• G-protein coupled receptors
• Ion channel receptors
• Enzyme receptors
• Receptors with associated tyrosine kinase

G protein-coupled recept ors: There are a variety of G protein-coupled receptors (G protein stands for guanosine triphosphate -binding protein). G-protein coupled receptors, in contrast to ion channel receptors, do not form channels or pores, but activate a downstream G-protein or protein kinase upon binding of their ligand. In this way, they modulate an intracellular signalling cascade by changing the concentration of secondary messenger substances. In addition, the membrane permeability can also be changed indirectly.

The signal transduction of the G-coupled receptors proceeds in 4 phases (see also G-protein-coupled receptors):

• The agonist triggers a conformational change by binding to the receptor.
• This conformational change activates the intracellularly associated G protein.
• The G protein breaks down into 2 protein subunits (Gβƴ and Gα), which can increase and decrease the concentration of intracellular messengers (second messengers).
• The signal terminates by hydrolysis of GTP (the alpha subunit has GTPase activity). The G protein returns to its inactive original state.

Examples of G protein-coupled receptors:

• G5-associated receptors: Binding of an agonist to the receptor stimulates adenylate cyclase via the alpha subunit of the G5 protein. This leads to an increase in cyclic adenosine 3,5-monophosphate (cAMP) synthesis. The increase in cAMP leads to activation of cAMP-dependent protein kinase A (PKA). PKA substrates include the L-type -Ca2+ channels in cardiac myocytes.
• Enzymes of fat and glycogen metabolism
• Myokinase in smooth muscle cells.
• Gi/o protein-associated receptors: activation of this type of receptor by an agonist leads to inhibition of the alpha-subunit of Gi/o proteins, adenyl cyclase resulting in a decrease in the synthesis of cAMP. A subunit of this G-protein can control several effectors, partly blocking partly activating them.

Ion channel recept ors (ionotropic receptors) These are "very fast receptors" that are effective within milliseconds. This type of receptor has a direct influence on ion channels. Ion channel and receptor are not structurally separate entities, but are part of the same protein complex. Thus, the associated protein complex(see exemplary figure of the nicotinic acetylcholine receptor of the motor end plate) includes the ion channel and the receptor. The ion channel-receptor complex usually consists of 5 subunits that penetrate the cell membrane. They are arranged so that their alpha-helical structure itself or associated channel-forming domains enclose a central pore (membrane channel). The binding site for the endogenous agonist of the receptor is located extracellularly at one of the channel subunits. Examples of inotropic receptors are the nicotinic acetylcholine receptor, the GABAA receptor whose ligand is gamma-aminobutyric acid. The binding site for the agonist(acetylcholine in the picture example) is found extracellularly at one of the channel subunits. When the agonist binds to its receptor, acetylcholine undergoes a lightning-like influx of Na+ ions and an outflow of K+ ions. Activation of the GABA receptor leads to an influx of chloride ions into the cell, their hyperpolarization and a decrease in cellular excitability).

Another important ion channel receptor is the serotonin receptor of the 5-HT3 type, which causes cellular excitation by increasing the transmembrane conductance for Na+ and K+.

Enzyme receptors: By definition, enzyme receptors are receptors with "inherent", i.e. inherent enzyme activity(see figure with schematic representation). This type of receptor (typical representatives are receptors for natriuretic peptides) binds the agonist with its extracellular domain. The intracellular domain has "inherent" enzyme activity, namely guanylate cyclase activity(inherent receptor). Stimulation of this membrane-bound guanylate cyclase leads to the formation of the second messenger cGMP. CGMP-dependent protein kinases (PKG) phosphorylate various protein substrates in smooth muscle cells. protein substrates in smooth muscle cells and thus cause smooth muscle cells to relax).

Receptors with associated tyrosinase activity: Receptors for erythropoietin, interferons and other cytokines as well as insulin have no "inherent enzyme activity". They bind their agonist and then secondarily activate a tyrosine kinase associated with the receptor protein, which tyrosine phosphorylates the receptor itself and other intracellular substrates. This creates binding sites for IRS (insulin receptor substrates) which, bound to effector molecules via the small G protein Ras, activate protein kinases B and C, which are responsible for insulin-induced changes in carbohydrate, lipid and protein metabolism.

Intracellular receptors: Steroid hormones, thyroid hormones, vitamin D and retinoids are so lipophilic that they can penetrate cell membranes. They can thus dock to intracellular receptors that are present in the cytosol bound to activating proteins. The docking of the agonist to its receptor initially leads to the detachment of inactivating proteins. The agonist-receptor complex then docks with another agonist-receptor complex and enters the nucleus as a dimer. There, this complex binds to specific DNA sequences and promotes or inhibits the transcription of certain target genes.

Receptor-like proteins: This term includes cellular proteins that do not mediate the effects of transmitters, hormones or cytokines, but have other roles in the cell. They include:

• Enzymes (Na+, K+ or ATPases).
• Transporters (e.g. the neuronal norepinephrine or serotonin transporters, which are blocked by certain antidepressants).
• Cellular structural proteins (e.g. microtubili blocked by vinca alkaloids or taxanes)

The term receptor used to be much broader. Receptors also included sensors such as motion sensors, strain sensors, pressure sensors, colour sensors, moisture sensors, joint sensors, hair follicle sensors, pressosensors. This has changed in recent years.