Mechanism of ionotropic receptors or ligand-gated ion channels (LGICs)

In pharmacology, receptors can be divided into 4 general groups:
1. Ion channels:

• Ligand gatedace

• Voltage gated

• Second messenger regulated

2. G protein coupled receptors
3. Receptor tyrosine kinase
4. Intracellular hormone receptors: like  the glucocorticoid receptor

The video animation below shows the activation of a ionotropic receptor or ligand-gated ion channel (LGIC):

An excerpt on the topic from Katzung’s textbook:

Ligand-Gated Channels
Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.
Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (AChR), which allows Na⁺ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential-a depolarization.

Mechanisms that Bacteria Use to develop antibiotic resistance

Mechanisms of Antimicrobial Resistance

Mutation

Destruction or Inactivation

Efflux ( 1:00)

Genetic Transfer

Conjugation

Transformation

Transduction

Cisplatin and its Mechanism of Action

Mechanism of Action.

Cisplatin, carboplatin, and oxaliplatin enter cells by diffusion, and by an active Cu2+ transporter (Kruh, 2003). Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by reaction with nucleophiles such as thiols. Chloride is replaced by water, yielding a positively charged molecule. In the primary cytotoxic reaction, the aquated species of the drug then reacts with nucleophilic sites on DNA and proteins. Aquation is favored at the low concentrations of chloride inside the cell and in the urine. High concentrations of chloride stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity (see below). Hydrolysis of carboplatin removes the bidentate cyclobutanedicarboxylato group; this activation reaction occurs slowly.

The platinum complexes can react with DNA, forming both intrastrand and interstrand cross-links. The N7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines on the same DNA strand; guanine-adenine cross-links also readily form and may be critical to cytotoxicity (Parker et al., 1991). The formation of interstrand cross-links is less favored. DNA adducts formed by cisplatin inhibit DNA replication and transcription and lead to breaks and miscoding, and if recognized by p53 and other checkpoint proteins, induction of apoptosis. Although no conclusive association between platinum-DNA adduct formation and efficacy has been documented, the ability of patients to form and sustain platinum adducts appears to be an important predictor of clinical response (Reed et al., 1986). Preclinical data suggest that the formation of the platinum-adenosine-to-guanosine adduct may be the most critical adduct in terms of cytotoxicity.

The specificity of cisplatin with regard to phase of the cell cycle appears to differ among cell types, although the effects of cross-linking are most pronounced during the S phase. Cisplatin is mutagenic, teratogenic, and carcinogenic. The use of cisplatin- or carboplatin-based chemotherapy for women with ovarian cancer is associated with a fourfold increased risk of developing secondary leukemia (Travis et al., 1999).

Source:Goodman And Gilman’s The Pharmacological Basis of Therapeutics

Happy Mothers Day !! Mothers --- We Salute You !!!

Happy Married Life !!