4.3:
Signal Transduction: Overview
Signal transduction is a process where the binding of an extracellular messenger initiates a series of molecular reactions, leading to a cellular response.
When an extracellular ligand or a drug binds a receptor, it changes the receptors' conformation to activate it. These receptors can be G protein–coupled receptors or GPCRs, enzyme-linked receptors, nuclear receptors, or ligand-gated ion channels.
The activated receptors transmit and amplify the signal in different ways. Ion channels facilitate ion movement across the cell, changing the membrane potential and mediating cellular activities like neurotransmission and muscle contraction.
GPCRs associate with heterotrimeric G proteins to interact with effectors and produce second messengers.
In contrast, the enzyme-linked receptors have intracellular kinase domains that phosphorylate multiple downstream effectors to modulate gene expression.
Alternatively, lipophilic drugs or steroids cross the bilayer to bind cytosolic nuclear receptors. The drug-receptor complexes translocate to the nucleus and regulate gene transcription.
4.3:
Signal Transduction: Overview
Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three steps: (1) reception, (2) transduction, and (3) response. In most signal reception, a membrane-impermeable molecule, or ligand, causes a change in a membrane receptor; however, some signaling molecules, such as hormones, can cross the membrane to reach their internal receptors. The membrane receptor then sends this signal to other cellular molecules, typically intracellular messengers, which convert the message into a cellular response. Commonly known receptors on the cell surface or inside the cell include G protein–coupled receptors (GPCRs), ligand-gated ion channels, enzyme-linked receptors, and nuclear receptors. GPCRs are membrane-spanning proteins with an extracellular binding ligand binding site. Most drugs target GPCR and activate or block its activity. Once activated, these receptors couple with heterotrimeric G proteins and activate them. The activated heterotrimeric G proteins then move across the membrane to stimulate various downstream effectors to generate second messengers. The second messengers, such as cyclic AMP, carry the signal to target proteins and elicit a cellular response.
Another group of receptors, ligand-gated ion channels, are involved in fast synaptic neurotransmission by rapidly changing the ion flow across the cell. Various drugs bind at the ligand binding site, allosteric site, or channel pore to regulate the opening and closing of the ion channel. This leads to membrane potential changes affecting cellular processes such as neurotransmission, muscle contraction, and muscle relaxation.
On the other hand, the enzyme-linked receptors are unique transmembrane receptors that either have an intracellular enzymatic domain or are attached to an enzyme to start a phosphorylation cascade, phosphorylating downstream protein substrates and activating them.. These receptors are involved in cell proliferation, growth, differentiation, repair, and immune responses.
Lastly, various lipophilic ligands and drugs diffuse through the membrane to bind and activate nuclear receptors in the cytosol or directly bind to DNA inside the nucleus. They are ligand-activated transcription factors that regulate the transcription of genes involved in reproduction and metabolic pathways.
The intracellular response generated through these different types of receptors includes changes at both gene and protein levels. The receptors also bind to a variety of ligands, ranging from neurotransmitters, hormones, vitamins, lipids, or lipoproteins. Pharmaceutical companies exploit this to design drugs of different structural and chemical properties, targeting specific signaling pathways involved in a particular disease.