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Preprint WatchMildNovember 7th, 2026

A Gαq/11-IP3R1-ANO1 pacemaking axis underlies pressure-induced lymphatic chronotropy

Davis, M. J.; Kim, H. J.; Li, M.; Castorena-Gonzalez, J. A.; Schulz, M. E.; Pea, G.; Pal, S.; Domeier, T.; Scallan, J.; Earley, S.; Zawieja, S. D.

A Gaq/11 to IP3R1 to ANO1 signalling axis is proposed to underlie pressure-induced chronotropy in lymphatic muscle cells, placing ANO1 as the effector channel for mechanosensitive lymphatic pacemaking.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint positions ANO1 as the terminal effector in lymphatic pacemaking, which would make it a candidate target for disorders of lymphatic transport. Claidex holds one ANO1 program failure, gdc-6988-ano1-tmem16a-bronchiectasis-copd-phase1-sponsor-termination, where a TMEM16A modulator was dropped during Phase 1. That termination was a sponsor decision rather than an efficacy readout, so it says little about ANO1 biology and a good deal about developability. The caution for any new ANO1 indication is that the channel is broadly expressed across smooth muscle and secretory epithelium, so an agent potent enough to alter lymphatic chronotropy will act well beyond the lymphatic vessel.

Abstract excerpt

The frequency of spontaneous lymphatic contractions is exquisitely sensitive to changes in intraluminal pressure, enabling lymph transport to be matched to the filling state of the lymphatic capillary network. The mechanistic basis of this mechanosensitive response was investigated using ex vivo contraction assays of mouse popliteal collecting vessels. Based on electrophysiological and transcriptional similarities between lymphatic muscle cells (LMCs) and arterial smooth muscle, we hypothesized that pressure-dependent chronotropy shares a parallel signaling process with pressure-induced arterial depolarization/constriction. Thus, we probed two potential mechanisms: 1) pressure-induced activation of mechanosensitive cation channels and 2) mechano-activation of GNAQ/GNA11-coupled G-protein receptors (GPCRs) that would generate second messengers to activate those channels. Contraction assays were combined with scRNAseq analysis of the respective targets and use of transgenic mice. Our findings rule out significant roles for the mechanosensitive channels implicated in arterial myogenic constriction as well as channels implicated in ionic pacemaking of other tissues. In contrast, smooth-muscle specific knock out or inhibition of ANO1, IP3R1 or GNAQ/GNA11 significantly abrogated pressure-induced chronotropy. These results support a scheme whereby mechano-activation of one or more GNAQ/GNA11-coupled GPCRs generates IP3, inducing sarcoplasmic reticulum Ca2+ release through IP3R1, which drives depolarization through the activation of ANO1 Cl- channels. The major GPCRs expressed in LMCs were identified and ranked by scRNAseq analysis but individual inhibition or knock out the top 7 candidates failed to significantly impair pressure-induced chronotropy. Our results implicate one or more GNAQ/GNA11-coupled GPCRs in mediating this mechanosensitive process, but the specific GPCRs remain to be identified.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.