Tpcn1

Two pore calcium channel protein 1 (Voltage-dependent calcium channel protein TPC1)

Spatial tier: REGION_BIASED · Class: ION_CHANNEL · Top region: AP (Area postrema) · Positive regions: 29/554

42.0Discovery Score
39.9Targetability Score
CEvidence grade C
What this means: Tpcn1: fine CCF profile is region-biased toward AP (top regions: AP, LM, ME, AOBgl, MMd); this is a discovery lead, not direct proof.

Function in AP: evidence, prediction, innovation

Gene function
Tpcn1 encodes two-pore channel 1, a Na+- and Ca2+-permeable channel of endosomal and lysosomal membranes. It is gated by PI(3,5)P2, modulated by NAADP via accessory NAADP-binding proteins, and regulated by mTOR with nutrient state. TPC1 shapes endolysosomal Ca2+ release, vesicle fusion, receptor recycling and autophagic flux.
Region function
The area postrema is a circumventricular organ in the dorsal medulla whose fenestrated capillaries let it sample blood-borne GDF15, amylin, GLP-1 and toxins. Its excitatory neurons project to the NTS and parabrachial nucleus to drive nausea, emesis, conditioned taste aversion and anorexia.
Published in this region
none No region-specific literature found. Mallmann and Klugbauer 2020 detected TPC1 protein broadly in mouse neocortex, cerebellum and hippocampus and found spatial learning deficits in Tpcn1-/- mice; Martucci et al. 2023 showed endolysosomal TPCs control oxytocin secretion from hypothalamic neurons.
Predicted function
Prediction: AP neurons are peptidergic and catecholaminergic and depend on dense-core vesicle trafficking and rapid recycling of GFRAL, CALCR and GLP1R after ligand exposure, so Tpcn1 most plausibly sets the gain of that vesicular Ca2+ signalling. Tpcn1 deletion or trans-Ned-19 should leave baseline feeding intact but blunt and shorten GDF15-, amylin- or LiCl-evoked taste aversion and anorexia, and slow tachyphylaxis to repeated GLP-1 receptor agonist dosing.
Innovation
★★★★★ 5/5 Endolysosomal two-pore channels have never been examined in the AP despite demonstrated control of hypothalamic neuropeptide secretion and the AP's role in incretin-drug side effects.
Tools
Tpcn1-/- and Tpcn1/Tpcn2 double-knockout mice (Klugbauer lab); NAADP antagonist trans-Ned-19; TPC blocker tetrandrine; PI(3,5)P2 and NAADP-AM activators; lysosome-targeted Ca2+ sensors; anti-TPC1 antibodies. No Cre driver.
References

Direct evidence located at the region

Tpcn1 Allen ISH at the CCF centroid of AP

Allen ISH experiment 69262231, section image 69430804 (section 157): the section that contains the CCF centroid of Area postrema according to the Allen image-to-atlas alignment (reference_to_image), with a 2 mm window around that point. Left: whole section, red box = window. Middle: ISH signal. Right: Allen's expression-mask view of the same window. open this image in the Allen viewer

Look it up yourself: Allen Mouse Brain ISH for Tpcn1Allen reference atlas: AP (structure 207)ABC Atlas MERFISH viewer(in the ABC Atlas choose dataset MERFISH-C57BL6J-638850-CCF, colour cells by gene "Tpcn1" or by parcellation_substructure "AP")All genes confined to AP + 3-D brain

Direct spatial evidence

MERFISH REGION LOCATOR
AP MERFISH region locator
Real single-cell MERFISH coordinates for the AP (Area postrema) section -- our own ground-truth data, showing exactly where this region sits, independent of whether the Allen ISH section below is easy to read.

Regional expression figure

Tpcn1 regional expression profile

Predicted WMB × fine-CCF profile; not direct full-transcriptome spatial measurement.

Spatial profile

AP
4.56
LM
3.61
ME
3.58
AOBgl
3.45
MMd
3.23
MT
3.2
OV
3.14
SSp-m1
3.12
PVp
3.03
ENTl1
2.97
AUDd1
2.97
VISpor1
2.95
NLOT1
2.93
SNr
2.91
MOp1
2.9
PL2/3
2.9
SG
2.88
SSs1
2.88
PL1
2.87
VISl1
2.87

Evidence and specificity

Evidence status
PREDICTED_FINE
Direct sources
None; predicted localization only
Exclusive threshold
12 positive regions out of 554
Spatial specificity
0.288
Top-region fraction
0.057
Filter status
PASS

Interpretation limits