itr-1
C. elegans
Inositol 1,4,5-trisphosphate receptor itr-1
What the model saw
Gene: itr-1 Organism: Caenorhabditis elegans Known functions: Inositol 1,4,5-trisphosphate receptor itr-1. calcium channel activity. calcium ion binding. inositol 1,4,5 trisphosphate binding. inositol 1,4,5-trisphosphate-gated calcium channel activity. monoatomic ion channel activity. myosin binding. phosphatidylinositol binding. protein binding.
View unredacted entry
Inositol 1,4,5-trisphosphate receptor itr-1. calcium channel activity. calcium ion binding. inositol 1,4,5 trisphosphate binding. inositol 1,4,5-trisphosphate-gated calcium channel activity. monoatomic ion channel activity. myosin binding. phosphatidylinositol binding. protein binding.
Solver output
ITR-1 is the C. elegans inositol 1,4,5-trisphosphate receptor (IP3R), a ligand-gated calcium channel on the ER membrane that releases Ca²⁺ in response to IP3 signaling. IP3 is generated downstream of phospholipase C activation, which is itself downstream of insulin/IGF-1-like signaling (IIS) via the DAF-2 pathway. Elevated IP3R/ITR-1 activity promotes calcium release that can activate downstream effectors reinforcing IIS, thereby suppressing DAF-16/FOXO nuclear localization and reducing stress resistance and longevity. Genetic reduction-of-function alleles of itr-1 in C. elegans have been shown to extend lifespan, consistent with dampened IIS-coupled calcium signaling allowing greater DAF-16 activity. Thus, the normal (wild-type) function of itr-1 — promoting IP3-gated Ca²⁺ release — acts to suppress longevity pathways, making it anti-longevity in its normal role; however, several studies also show itr-1 interacts with the germline and other pathways, and some gain-of-function contexts extend life. The predominant genetic evidence places wild-type itr-1 activity as opposing longevity through reinforcement of IIS and suppression of DAF-16.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model correctly predicts "pro_longevity" for itr-1, but the mechanistic reasoning is confused and partially contradictory. The model initially argues that wild-type itr-1 is anti-longevity (suppresses DAF-16), but then concludes it is pro_longevity. The actual evidence in C. elegans is that itr-1 gain-of-function extends lifespan, making it pro-longevity — the opposite of what the model's main mechanistic argument suggests. The model's reasoning about reduction-of-function extending lifespan would make itr-1 anti-longevity, yet it concludes pro_longevity. The model seems to contradict itself and arrives at the correct answer despite flawed reasoning. The actual mechanism involves itr-1 gain-of-function extending lifespan through calcium signaling pathways, possibly involving the germline or intestinal signaling, not simply through suppression of IIS. The model's mechanistic framework is largely incorrect.
Raw API responses
solver
{
"reasoning": "ITR-1 is the C. elegans inositol 1,4,5-trisphosphate receptor (IP3R), a ligand-gated calcium channel on the ER membrane that releases Ca²⁺ in response to IP3 signaling. IP3 is generated downstream of phospholipase C activation, which is itself downstream of insulin/IGF-1-like signaling (IIS) via the DAF-2 pathway. Elevated IP3R/ITR-1 activity promotes calcium release that can activate downstream effectors reinforcing IIS, thereby suppressing DAF-16/FOXO nuclear localization and reducing stress resistance and longevity. Genetic reduction-of-function alleles of itr-1 in C. elegans have been shown to extend lifespan, consistent with dampened IIS-coupled calcium signaling allowing greater DAF-16 activity. Thus, the normal (wild-type) function of itr-1 — promoting IP3-gated Ca²⁺ release — acts to suppress longevity pathways, making it anti-longevity in its normal role; however, several studies also show itr-1 interacts with the germline and other pathways, and some gain-of-function contexts extend life. The predominant genetic evidence places wild-type itr-1 activity as opposing longevity through reinforcement of IIS and suppression of DAF-16.",
"confidence": 0.65,
"key_pathways": [
"insulin/IGF-1 signaling (IIS) / DAF-2–DAF-16 axis",
"IP3-gated ER calcium release",
"phosphatidylinositol signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicts \"pro_longevity\" for itr-1, but the mechanistic reasoning is confused and partially contradictory. The model initially argues that wild-type itr-1 is anti-longevity (suppresses DAF-16), but then concludes it is pro_longevity. The actual evidence in C. elegans is that itr-1 gain-of-function extends lifespan, making it pro-longevity — the opposite of what the model's main mechanistic argument suggests. The model's reasoning about reduction-of-function extending lifespan would make itr-1 anti-longevity, yet it concludes pro_longevity. The model seems to contradict itself and arrives at the correct answer despite flawed reasoning. The actual mechanism involves itr-1 gain-of-function extending lifespan through calcium signaling pathways, possibly involving the germline or intestinal signaling, not simply through suppression of IIS. The model's mechanistic framework is largely incorrect.",
"failure_mode": "right_answer_wrong_reasoning",
"answer_correct": true,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}