Basics of Signal Transduction

A cell for its own survival performs gene transcription, connects via cell signaling, maintains its ionic balance, and undergo many such physiological functions. For all these, proper signal transduction is crucial and that occurs via receptors. The receptors' various components and its mechanistic pathway will be discussed here:

• Receptors on the surface of cells have two major functions:

          (1) Ligand Binding      (2) Message Propagation

• Two functional domains are present within the receptor:

          (1) A Ligand Binding Domain (LBD)   (2) An effector domain

SIGNAL TRANSDUCTION PATHWAY:

• The actions of a receptor imply directly on its cellular target, on effector proteins, or on Transducers (intermediate cellular signaling molecules).

• In maximum cases, the ultimate target of a receptor is an enzyme, ion channel or transport protein that create/move/degrade small molecule or ion called as Second Messenger. These Second messengers convey information to a wide range of targets that can fuse multiple signals.
• Receptors have a very interesting property of being capable of amplification of signals. Neurotransmitters, hormones, and other ligands at LBD of a receptor are present in very low concentrations (nM to μM levels), but the signal transduction pathway contains enzymes, enzyme cascades that amplify the particular signal.

G-PROTEIN COUPLED RECEPTOR (GPCR) :

• It is also called as Metabotropic or 7-Transmembrane domain receptors.
• It is spread over the cell membrane as a bundle of 7 α-helices.
• Some examples as the ligands of GPCR include – Neurotransmitters (Acetylcholine, Norepinephrine, GABA), all eicosanoids, peptide hormones, opioids, etc.
• GPCRs coupled with different G-proteins and bring about distinct cellular effects.

G-Proteins: These are the signal transducers who supply the information from the agonist bound receptor to one or more effectors. G-Proteins are called so due to their interaction with guanine nucleotides (GTP and GDP).

Signal Transduction Pathway:

1. G-protein has 3 subunits (α, β, γ) which are anchored to the membrane through attached lipid residues.
2. INITIATION: Guanine nucleotides bind to α-subunit by replacing GDP→GTP.
3. ACTIVATION: When an agonist binds with the receptor, the GTP- binding to the α-subunit is resulting in detachment of α-GTP complex from the βγ complex. This state is called the Active Form of G-Protein.
4. SIGNAL TRANSDUCTION: This complex can then interact with other enzymes, ion channels, or simply effectors and in turn, the effectors can produce Second messengers that further activate other effectors and produces a Signal-cascade.
5. Adenylyl cyclase is activated by G_s and inhibited by G_i which produces cAMP (second messenger), G_q activates PLC ( Phospholipase C) thus producing two other second messengers, IP₃ ( inositol triphosphate) and DAG (diacylglycerol). IP₃ regulates intracellular free Ca²⁺ concentration and some protein kinases too.
6. REGULATION: A family of 20 cellular proteins called as Regulators of G-Protein Signalling (RGS) controls the downregulation of GPCRs.
7. They hydrolyze GTP→GDP, GRKs are one type of RGS that phosphorylate the C-terminal tail of receptor and introduce Arrestins which bind to the receptor on the internal surface and inhibit signaling by displacing G-Proteins.

fig-1: Signal Transduction Pathway of GPCR

We will upload the rest of the contents related to this i.e., targets of GPCR, its desensitization, etc. very soon. So stay connected for the rest of it and for more such contents.

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