Browsing Pathways

PANoptosis emerges as a major integrated cell-death response driven by excitotoxicity, inflammation, and mitochondrial dysfunction. During ischemia and reperfusion, excessive glutamate release overstimulates NMDA receptors, causing massive Ca²⁺ influx into neurons and mitochondrial overload. This leads to mitochondrial permeability transition pore opening, cytochrome c release, and ROS generation, priming the cell for apoptosis and amplifying inflammatory signaling. Meanwhile, damage-associated molecular patterns generated during stroke activate ZBP1, which in turn triggers assembly of the PANoptosome, a multiprotein platform containing ASC, Caspase-8, and the RIP1–RIP3 complex. Once active, the PANoptosome coordinates apoptosis (via Caspase-8 and Caspase-3), pyroptosis (via ASC-mediated Caspase-1 activation leading to Gasdermin-D pores and cytokine release), and necroptosis (via RIP1–RIP3–MLKL–mediated membrane rupture). In stroke, this convergence of mitochondrial injury, Ca²⁺ dysregulation, and innate immune activation makes PANoptosis a potent driver of neuronal loss and secondary inflammation, contributing to the worsening of tissue damage beyond the initial ischemic event.

This pathway describes the molecular pathway of steroid synthesis in human ovarian cells, specifically within theca and granulosa cells of the ovary. The process begins when luteinizing hormone (LH) binds to its receptor on the theca cell membrane, activating a G protein complex, which in turn stimulates adenylate cyclase to produce cAMP. The increase in cAMP activates protein kinase A (PKA), which then moves from the cytosol into the nucleus to phosphorylate CREB, a transcription factor. Phosphorylated CREB promotes expression of the StAR (Steroidogenic Acute Regulatory) protein, which is transported to the mitochondria to facilitate cholesterol transfer across mitochondrial membranes, the first step in steroid hormone synthesis. Cholesterol is converted to pregnenolone, which is then processed through a series of enzymatic reactions to form androstenedione in the theca cells. Androstenedione is transported to the granulosa cells, where it is converted into estrone and estradiol, the primary estrogens. These hormones are ultimately secreted into the bloodstream, completing the pathway that links LH stimulation to estrogen production and release.

Glucagon is a peptide notable for its action in glucose homeostasis. It is secreted in response to a multitude of different signals, predominantly in low glucose concentration. It is also known to secrete in response to free fatty acids and stress. In hypoglycemic conditions, the secretion of glucagon increases to create increased hepatic glucose production. Glucagon binds the transmembrane receptor on the plasma membrane of the cell to generate the conformational change that initiates the Gas coupled proteins.

The prolactin signaling pathway in Homo sapiens begins when prolactin, secreted by the pituitary gland, binds to and activates prolactin receptor (PRLR) dimers on mammary epithelial cells. This triggers recruitment and phosphorylation of the tyrosine kinase JAK2, which in turn phosphorylates both the receptor and STAT5A. Activated STAT5A forms dimers that translocate to the nucleus, where they regulate transcription of key genes involved in lactation (such as β-casein), cell survival (BCL2), cell cycle progression (Cyclin D1), and negative feedback regulators (SOCS2, SOCS3, CISH, IRF1). In parallel, PRLR signaling activates the MAPK/ERK cascade through GRB2–SOS–RAS–RAF–MEK–ERK, promoting cell proliferation and differentiation. The receptor also engages the PI3K–AKT–mTOR pathway via IRS1, enhancing cell survival, metabolism, and protein synthesis. Together, these interconnected sub-pathways coordinate mammary gland development, lactation, and cellular homeostasis, while negative regulators such as SOCS proteins, PIAS, and phosphatases prevent overactivation of the pathway.

This pathway illustrates the multifaceted interactions between streptomycin—an aminoglycoside antibiotic—and Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv), highlighting its antibacterial mechanism, molecular targets, and downstream cellular consequences. Once inside the cytoplasm, streptomycin binds to the 16S rRNA component of the 30S ribosomal subunit, specifically interacting with the S12 protein and the decoding site of the ribosome. This interaction alters ribosomal conformation, leading to misreading of mRNA codons and premature termination of peptide synthesis. At the molecular interaction level, the antibiotic’s binding interferes with the fidelity of translation and promotes the incorporation of incorrect amino acids, producing nonfunctional or toxic proteins. These aberrant proteins can integrate into the bacterial membrane, increasing permeability and further enhancing streptomycin uptake—creating a self-amplifying bactericidal effect. At the cellular outcome level, inhibition of accurate protein synthesis leads to loss of metabolic integrity, disruption of essential enzymatic systems, and eventual cell death. In Mycobacterium tuberculosis, streptomycin is particularly effective against actively dividing cells, though its efficacy diminishes against nonreplicating or intracellular bacilli due to limited penetration and lower metabolic activity. Host pharmacodynamics reflect streptomycin’s poor oral absorption and reliance on parenteral administration. In humans, the drug distributes primarily in extracellular fluids and is excreted unchanged via the kidneys. Ototoxicity and nephrotoxicity are notable dose-limiting adverse effects, arising from accumulation in cochlear and renal tissues. Together, this pathway represents the molecular cascade by which streptomycin exerts its bactericidal action—binding to the ribosome, corrupting protein synthesis, and destabilizing cellular function—while also illustrating the bacterial adaptations that modulate drug sensitivity during tuberculosis therapy.

Ethambutol is a bacteriostatic antitubercular agent whose primary action targets the unique mycobacterial cell wall. After entering Mycobacterium tuberculosis cells, ethambutol specifically inhibits arabinosyltransferase enzymes (encoded by the embA, embB, and embC genes), which are essential for the polymerization of arabinogalactan and lipoarabinomannan, two major cell wall components. This inhibition disrupts the biosynthesis of arabinogalactan, undermining the structural integrity of the cell wall and significantly increasing its permeability. Decreased arabinogalactan synthesis also results in reduced anchoring sites for mycolic acids, impairing the stability of the mycolyl-arabinogalactan–peptidoglycan complex that protects the cell.

The pyrazinamide (PZA) pathway plays a crucial role in the treatment of Mycobacterium tuberculosis infection. Pyrazinamide is a prodrug that requires activation by the bacterial enzyme pyrazinamidase/nicotinamidase (PncA). This enzyme converts PZA into its active form, pyrazinoic acid (POA), which accumulates inside the bacterium. In the acidic environment of infected tissues and within macrophages, POA interferes with several vital processes, including membrane energetics, fatty acid synthesis, and trans-translation, ultimately leading to bacterial death. Mutations in the pncA gene are the primary cause of PZA resistance, as they prevent activation of the drug. Because PZA is uniquely effective against dormant and slowly replicating bacteria in acidic environments, it is an essential component of first-line tuberculosis therapy, helping shorten treatment duration and improve cure rates.

Isoniazid is an antibiotic used to treat the mycobacterial infection tuberculosis. After oral ingestion it begins its mechanism of action as a prodrug. It needs to be activated by the bacterial catalase KatG. Once it is activated it initiates its antibiotic properties by inhibiting the synthesis of mycolic acids, an essential component of the mycobacterial cell wall, through the formation of an INH-NAD adduct that tightly inhibits InhA, the enoyl-acyl carrier protein reductase in Mycobacterium tuberculosis.

The long-term potentiation (LTP) pathway represents a key molecular mechanism underlying synaptic plasticity, learning, and memory formation in the human brain. LTP begins with the release of L-glutamic acid (glutamate) from the presynaptic neuron into the synaptic cleft, where it binds to and activates both the AMPA and NMDA glutamate receptors on the postsynaptic membrane. Activation of AMPA receptors allows the influx of sodium ions (Na⁺) into the neuron, depolarizing the postsynaptic membrane. This depolarization removes the magnesium (Mg²⁺) block from NMDA receptors, enabling their activation by glutamate and allowing calcium ions (Ca²⁺) to flow into the postsynaptic cytosol. The rise in intracellular calcium acts as a crucial second messenger, triggering downstream signaling cascades, including the ERK/MAPK pathway. Activated ERK phosphorylates CREB (cAMP response element-binding protein), which then translocates from the cytoplasm to the nucleus. In the nucleus, phosphorylated CREB promotes transcription of genes necessary for synaptic growth and stabilization, reinforcing synaptic strength over time. Overall, the LTP pathway integrates glutamate receptor activation, ion transport, and calcium-dependent signaling to induce lasting changes in synaptic efficiency. This process underlies the cellular basis for long-term memory storage and neuronal adaptability in the human brain.

Olfaction is the chemosensory process that enables the detection of airborne, volatile molecules at very low concentrations. The OR1L3 (Olfactory Receptor 1L3) gene encodes a G-protein-coupled receptor (GPCR) that participates in this detection by binding specific odorant molecules. OR1L3 is expressed on the cilia of olfactory sensory neurons within the olfactory epithelium of the nasal cavity. When odorant molecules enter the nasal cavity and dissolve in the mucus layer, certain ligands interact specifically with the OR1L3 receptor. This binding activates the olfactory G-protein (Golf), which stimulates adenylate cyclase to produce cyclic AMP (cAMP). The increase in intracellular cAMP concentration opens cyclic nucleotide–gated ion channels, allowing sodium (Na⁺) and calcium (Ca²⁺) ions to flow into the neuron. The resulting ionic influx depolarizes the cell membrane. If the depolarization reaches threshold, it triggers an action potential that travels along the olfactory nerve to the olfactory bulb. From there, the signal is transmitted to higher-order brain regions, such as the olfactory cortex, where it contributes to the perception of a distinct odor. The OR1L3 receptor has been shown to respond to several floral and aromatic compounds, including helional, cinnamaldehyde, and citronellol. These odorants are commonly described as having fresh, floral, and aldehydic notes, suggesting that OR1L3 contributes to the detection of pleasant, perfume-like scents. Variations in OR1L3 gene expression or sequence among individuals may influence sensitivity and perception of these types of odors.