Scope decisions recorded for the next curator. The airway restriction is the substantive one, and it is not the obvious reading of the project rule that one receptor family plus one direction of pharmacological action makes one module. A census of the corpus at the time this module was written found antimuscarinic drugs used for four mechanistically disjoint purposes, which would share this trigger and diverge at the effector: airway bronchodilation, 3 entries; detrusor overactivity and neurogenic bladder, 11; striatal cholinergic blockade in dystonia and related movement disorders, chiefly trihexyphenidyl, 20; and reversal of a cholinergic crisis with atropine, 10, in organophosphate and nerve agent poisoning, scorpion envenomation and vagally mediated bradycardia. The airway arm is the smallest of the four, and only Chronic_Obstructive_Pulmonary_Disease carries a treatment specific enough to wire: the other two airway entries bind no agent on the relevant treatment. So this module is scoped to the arm the Workstream A queue row named rather than to the arm where the class is most used, and that is a decision taken on the queue row's wording, not on the biology. Whether the other three arms become modules of their own or further effector arms off a shared trigger is an open question on the project page, and it bites harder here than it did for beta2 adrenergic receptor agonism, where the airway was the dominant use rather than the smallest. Several of the crisis-reversal entries already model the agonist side, with nodes named for muscarinic receptor overstimulation that atropine reverses; those are the same pattern at the opposite polarity and would conform to a trigger of their own, not to this one. The transducer step is sourced rather than assumed, and two things about those sources are worth knowing. The M3-Gq/11-phospholipase C coupling is quoted from equine airway tissue, where the sentence treats the coupling as the established pathway it set out to measure rather than as a species-specific finding; and the chain through IP3 to released calcium is quoted from a study of airway smooth muscle cells whose own novelty is that membrane depolarisation can drive that chain without an agonist, so it is cited for the chain and not for its headline. The depolarisation study (PMID:19549818) does not state the species of its cell preparation, although PubMed indexes that study under the MeSH descriptor Mice, so its cells are taken to be murine. The equine study (PMID:17803731) concerns equine tissue and is not read as describing the same preparation. An earlier draft left this step with no evidence of its own while binding GO terms for Gq-coupled phospholipase C signalling and calcium release, which made an unsourced claim look grounded: Gq coupling does not follow from a source saying only that the receptors are G-protein-coupled, since the M2 subtype named in the same sentence is Gi-coupled. Mucus secretion is carried as a second effector arm off the trigger because the same cited sentence names contraction and mucus secretion together, so the arm is sourced rather than inferred. No adverse-effect node is included: the antimuscarinic effects of inhaled therapy are real, but no abstract cited here states them, and an unsourced node would have been the one claim an ontology binding made look grounded.
Muscarinic Antagonist Occupancy of Airway M3 Receptors
trigger
An inhaled antimuscarinic binds the muscarinic acetylcholine receptor on airway smooth muscle and prevents acetylcholine acting there. The airway carries M1, M2 and M3 subtypes and the contractile response is M3-mediated, which is the subtype bound here; the agents range from short-acting ipratropium to the long-acting antagonists given once daily, and they antagonise the subtypes with differing kinetic selectivity rather than binding M3 alone. What the occupancy removes is a standing vagal tone rather than an episodic stimulus, which is why the effect reads as a withdrawal of contraction rather than as relaxation driven by the drug.
Downstream
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Loss of Gq-Coupled Phospholipase C Signalling and Calcium Release
Blocking the receptor removes the Gq-coupled signalling it initiates. The cited study measured that coupling in unblocked tissue, so it establishes the pathway the antagonist interrupts rather than the blocked state itself, which is why this edge is graded indirect.
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Reduced Cholinergic Mucus Secretion
The same receptors regulate mucus secretion as well as contraction, so the occupancy has a second effector arm. It is carried because the cited sentence names both, not because secretion was inferred from the contraction arm.
Show evidence (2 references)
"Orally inhaled tiotropium bromide antagonizes the muscarinic M(1), M(2), and M(3) receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction."
Names an antimuscarinic of this class antagonising the airway smooth muscle muscarinic receptors and reversing vagally mediated bronchoconstriction, which is exactly the occupancy this node represents.
"Targets of these drugs are G-protein-coupled muscarinic M(1), M(2) and M(3) receptors in the airways, which have long been recognized to regulate vagally-induced airway smooth muscle contraction and mucus secretion."
Names the receptors the antimuscarinic bronchodilator class acts on and what they regulate in the airway, which is the occupancy this node represents.
Loss of Gq-Coupled Phospholipase C Signalling and Calcium Release
effector
With the receptor blocked, the phospholipase C-activating arm it drives falls away and the cytosolic calcium rise that sustains contractile tone is not generated.
Downstream
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Withdrawal of Cholinergic Airway Smooth Muscle Contraction
Without the calcium signal the contractile apparatus is not driven, and the standing cholinergic contraction is withdrawn.
Show evidence (2 references)
"The M2-mediated inhibition of adenylate cyclase (AC) as well as the M3-receptor-G(q/11)-phospholipase C (PLC) activity was not different between RAO and control airway tissues."
States the M3-receptor-Gq/11-phospholipase C coupling in airway tissue directly, which is the transducer step this node names. Equine airway tissue; the sentence treats the coupling as the established pathway it measured, not as a species-specific finding.
"This format of local Ca(2+) release results from a direct activation of G protein-coupled, M(3) muscarinic receptors in the absence of exogenous agonists, which causes activation of Gq proteins and phospholipase C, and generation of inositol 1,4,5-triphosphate (IP(3)), inducing initial Ca(2+)..."
Carries the rest of the chain this node asserts: M3 receptors activating Gq and phospholipase C, generating IP3, and releasing sequestered calcium, in airway smooth muscle cells. Quoted for that chain rather than for the paper's own finding, which is that depolarisation can drive it without an agonist.
Withdrawal of Cholinergic Airway Smooth Muscle Contraction
central effector
The standing vagal contraction of airway smooth muscle is removed. This is the key conformance target: a disorder whose airway obstruction carries a cholinergic component conforms here, and the node is the state the drug produces rather than the drug's occupancy.
Downstream
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Bronchodilation and Relief of Airflow Obstruction
Relaxation of the airway smooth muscle widens the lumen and relieves obstruction, which is the clinical effect the class is given for.
Reduced Cholinergic Mucus Secretion
effector
The second arm of the occupancy. The same airway muscarinic receptors regulate mucus secretion, so blockade reduces it. The arm is kept separate from the contractile chain because it reaches the clinical picture by a different route and is not a step toward bronchodilation.
Bronchodilation and Relief of Airflow Obstruction
consequence
Measured as an improvement in expiratory flow and felt as reduced breathlessness. With a long-acting antagonist the effect is sustained across a dosing interval of a day, which is what makes the class a maintenance rather than a rescue therapy.
Show evidence (1 reference)
"Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours"
Names the sustained bronchodilation this node describes and the once-daily interval that follows from it.