Biological Membranes - A. N. Ogurtsov 2012

Electrogenesis of Biomembranes
Mechanisms of Intercellular Signaling
Transmitters

To respond to Changes in external conditions or to coordinate cellular activity within a multicellular Organism, Cells need to receive and transmit information. To this end, cells constantly exchange chemical signals known as transmitters.

Transmitters are classified in various ways. For instance, they can be categorized according to their lifespan within the organism.

The minimum lifespan is observed in transmitters used within intercellular synaptic clefts that are about 100 nm wide, amounting to ~10^-2-10^-4 s.

Hormones represent the opposite case, where a transmitter persists in the organism for minutes or even hours. Hormones are secreted into the bloodstream and distributed to body Tissues via Blood flow. Most hormones are produced by specialized Endocrine glands.

Paracrine transmitters also have a relatively long lifespan, but instead of being released into the blood, they are secreted into specific tissues and diffuse within that tissue.

Another method of classifying signaling mechanisms is based on the Location and Specificity of the receptors that receive the chemical signal. There are Three types of receptors for transmitters:

1) ionotropic receptors of the outer Cell membrane;

2) metabotropic receptors of the outer cell membrane;

3) intracellular receptors.

Ionotropic receptors of the outer cell membrane are Ion Channels that open As a result of the specific binding of a given transmitter to the exoplasmic domain of such channel protein. Below, we will examine a typical example: the nicotinic Acetylcholine Receptor.

The MECHANISM OF ACTION of ionotropic outer cell Membrane Receptors is similar to the Ligand-gated channels discussed above: the Inositol trisphosphate-gated channel (Figure 140) and the cAMP-gated channel (Figure 145). The difference, however, is that these Two Types of channels are opened by cytosolic molecules, whereas ionotropic outer cell membrane receptors are controlled by extracellular metabolites.

Metabotropic receptors of the outer cell membrane are always coupled to cellular Enzymes. Receptors of this type have already been encountered above: the ADP receptor activates the G_q protein and subsequently PLCß phospholipase (Figure 139); the odorant receptor (Figure 145) and the ß-adrenergic receptor are coupled to G_s and further to adenylate cyclase, which synthesizes cAMP. Tyrosine Kinase Receptors are protein Kinases themselves, which are activated by binding to their ligands (such as the PDGF factor in Figure 147).

The α-adrenergic receptor (in a manner entirely analogous to the Scheme for the ADP receptor (Figure 139)), in response to binding with noradrenaline (Figure 152), activates the G_q protein and then PLCß phospholipase, which leads to an increased concentration of inositol trisphosphate in the Cytosol, the opening of inositol trisphosphate-gated calcium channels, and an elevation of calcium concentration in the cytosol (Figure 140).

The α and ß adrenergic receptors are similar but distinct receptor Proteins. The α-adrenergic receptor binds to noradrenaline, while the ß-adrenergic receptor binds to adrenaline.

Intracellular receptors are located inside The Cell (in the cytosol or nucleoplasm) and bind transmitters that have diffused across The Plasma Membrane. Upon binding with transmitters, these receptors activate specific enzymes. Examples of such receptors include the nitric oxide (NO) receptor and steroid Hormone Receptors.

NO acts as a signal transmitter in many tissues. It is not stored in the organism but is instead synthesized from Arginine by the enzyme NO synthase precisely where it is needed. Nitric oxide easily diffuses through Plasma Membranes and binds to cytosolic protein NO receptors. For instance, the binding of NO to the enzyme guanylate cyclase activates it, catalyzing The conversion of GTP into the intracellular messenger cyclic guanosine monophosphate, cGMP.

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Figure 152 - Main Neurotransmitters

Steroid Hormones bind to intracellular steroid hormone receptors. For example, the cytosolic glucocorticoid receptor, upon binding to these hormones (such as hydrocortisone, corticosterone, and others synthesized by the adrenal cortex cells), transitions into an active form. It can then pass through the nuclear pore into the Cell Nucleus, where it binds to DNA at specific HRE (hormone response element) enhancer sites, stimulating the METABOLISM/31.html">Transcription of genes responsible for carbohydrate and Protein metabolism (see [2] clause 3.5).

Synaptic neurotransmitters. Signal transmission between Neurons and from motor neurons to Muscle cells occurs at specialized contacts called synapses, utilizing transmitter molecules known as neurotransmitters.

There are numerous small molecules that function as neurotransmitters (Figure 152).

With the exception of acetylcholine, all other neurotransmitters are Amino Acids or Amino Acid Derivatives. Thus, dopamine, adrenaline, and noradrenaline are synthesized from tyrosine, serotonin from Tryptophan, histamine from Histidine, and γ-aminobutyric acid (GABA) from glutamic acid. NUCLEOTIDES such as ATP, along with the corresponding nucleosides with fewer phosphate groups, are also utilized as neurotransmitters. As a rule, each neuron synthesizes only one type of neurotransmitter.

All "classic" neurotransmitters are synthesized in the neuron's cytosol and then imported into synaptic vesicles at the axon terminals, where they are stored until use (until the arrival of a Nerve Impulse). These vesicles, 40-50 nm in diameter, feature an increased lumen acidity generated by V-type proton pumps operating in the membranes of these vesicles.

Similarly to metabolite accumulation systems in plant vacuoles (Figure 105), the proton gradient established by these pumps (where the proton concentration in the lumen of the secretory vesicle is higher than in the cytosol) drives the import of neurotransmitters from the cytosol into the secretory vesicle lumen via H⁺-coupled antiporters located in the vesicle membrane.

For instance, synaptic vesicles accumulate acetylcholine from the cytosol via an H⁺/acetylcholine antiporter in the vesicular membrane. Acetylcholine itself is synthesized in the cytosol from acetyl-CoA and Choline in a reaction catalyzed by acetyltransferase.

It is noteworthy that the Gene encoding the antiporter protein is located within the first intron of the gene encoding acetyltransferase. This evolutionary mechanism ensured the precise co-ordination of expression for these two proteins. Other neurotransmitters employ distinct H⁺/neurotransmitter antiporters.