Biosignalling

Biosignaling is a process in which cells receive and act on signals. Proteins participate in biosignaling in different capacities, including acting as extracellular ligands, transporters for facilitated diffusion, receptor proteins, and second messengers.4 The proteins involved in biosignaling can have functions in substrate binding or enzymatic activity. Ion channels are proteins that create specific pathways for charged molecules. They are classified into three main groups, which have different mechanisms of opening, but all permit facilitated diffusion of charged particles. Facilitated diffusion, a type of passive transport, is the diffusion of molecules down a concentration gradient through a pore in the membrane created by this transmembrane protein. It is used for molecules that are impermeable to the membrane (large, polar, or charged). Facilitated diffusion allows integral membrane proteins to serve as channels for these substrates to avoid the hydrophobic fatty acid tails of the phospholipid bilayer. The three main types of ion channels are ungated, voltage-gated, and ligand-gated.4

As their name suggests, ungated channels have no gates and are therefore unregulated. For example, all cells possess ungated potassium channels. This means there will be a net efflux of potassium ions through these channels unless potassium is at equilibrium. In voltage-gated channels, the gate is regulated by the membrane potential change near the channel.4 For example, many excitable cells such as neurons possess voltage-gated sodium channels. The channels are closed under resting conditions, but membrane depolarization causes a protein conformation change that allows them to quickly open and then quickly close as the voltage increases. Voltage-gated nonspecific sodium–potassium channels are found in cells of the sinoatrial node of the heart. Here, they serve as the pacemaker current; as the voltage drops, these channels open to bring the cell back to threshold and fire another action potential. For ligand-gated channels, the binding of a specific substance or ligand to the channel causes it to open or close.4 For example, neurotransmitters act at ligand-gated channels at the postsynaptic membrane. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) binds to a chloride channel and opens it.

Membrane receptors may also display catalytic activity in response to ligand binding. There are three main domains to these enzyme-linked receptors: a membrane-spanning domain, a ligand-binding domain, and a catalytic domain. The receptor in the cell membrane is held in place by the membrane-spanning domain. An appropriate ligand will stimulate the ligand-binding domain which will induce a conformational change to activate the catalytic domain. The second messenger cascade is usually initiated as a result.  Classic examples are receptor tyrosine kinases (RTKs). RTKs are made up of of a monomer that dimerizes upon ligand binding. The active form is the dimer, that phosphorylates extra cellular enzymes, including the receptor itself (autophosphorylation). Serine/threonine-specific protein kinases and receptor tyrosine phosphatases are examples of other classes of enzyme-linked receptors. Biosignaling can make use of either existing gradients (ion channels) or second messenger cascades (enzyme-linked receptors and G protein-coupled receptors). G protein-coupled receptors (GPCRs) are a family of integral membrane proteins that are utilised in signal transduction.4 A seven membrane-spanning α-helices is a common characteristic of this family. The receptors differ in specificity of the ligand- binding area found on the extracellular surface of the cell. In order for GPCRs to transmit signals to an effector in the cell, they utilize a heterotrimeric G protein. G proteins are named for their intracellular link to guanine nucleotides (GDP and GTP). The binding of a ligand increases the affinity of the receptor for the G protein. The binding of the G protein represents a switch to the active state and affects the intracellular signaling pathway. There are several different G proteins that can result in either stimulation or inhibition of the signaling pathway. There are three main types of G proteins:

1) Gs stimulates adenylate cyclase, which increases levels of cAMP in the cell

2) Gi inhibits adenylate cyclase, which decreases levels of cAMP in the cell

3) Gq activates phospholipase C, which cleaves a phospholipid from the membrane to form PIP2. PIP2 is then cleaved into DAG and IP3; IP3 can open calcium channels in the endoplasmic reticulum, increasing calcium levels in the cell

 

References

1) Dorland’s (2012). Dorland’s Illustrated Medical Dictionary (32nd ed.). Elsevier Saunders.

p.1862.

2) Black, J.A., Sontheimer, H., Oh, Y., and Waxman, S.G. (1995). In The Axon, S. Waxman, J. Kocsis, and P. Stys, eds. Oxford University Press, New York, pp. 116–143.

3) Jessen KR, Mirsky R (August 1980). “Glial cells in the enteric nervous system contain glial fibrillary acidic protein”. Nature. 736–7

4) Hille, Bertil (2001) [1984]. Ion Channels of Excitable Membranes (3rd ed.). Sunderland,

Mass: Sinauer Associates, Inc. p. 5.

5) NV, B. (2002). Medical Biochemistry. San Diego: Harcourt/Academic Press. (lipid)

6)  Vander, Arthur (2008). Vander’s Human Physiology: the mechanisms of body function. Boston: McGraw-Hill Higher Education. pp. 345-347

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