# Pharmacological Diversity of nAChRs in Clade III Nematodes: Brugia malayi

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2021 · $382,500

## Abstract

Project Summary
1. Cholinergic anthelmintics, including levamisole and pyrantel, are used for the control of
 nematode parasites. We have found that cholinergic anthelmintics are not a homogenous
 functional class of drugs. These anthelmintics select for different subtypes of acetylcholine-
 gated ion-channel receptors (nAChRs) in muscle of parasitic nematodes. The different
 nAChR subtypes are produced by varied combinations of five subunit proteins: each subunit
 may be produced by a different gene. We will exploit our advances with RNAi, quantitative
 motility studies, molecular pharmacology and patch-clamp to study the diversity and dynamic
 nature of nAChR subtypes of Brugia malayi: a parasite that causes lymphatic filariasis. This
 parasite is an excellent specific and general nematode parasite model. It is tractable to study
 with techniques that permit functional studies of genes that produce the different subunits of
 the nAChR subtypes involved in parasite neuromuscular transmission.
2. The classic cholinergic anthelmintic, levamisole, selectively activates muscle L-subytpe
 nAChRs, producing spastic contraction in parasitic nematodes. In Brugia adults, responses to
 levamisole decline over an hour, but responses to other cholinergic anthelmintics do not.
 Why is there this loss of anthelmintic effect (tachyphylaxis) and why is there a difference
 between cholinergic anthelmintics? Here we will identify the dynamic functions and
 interactions of different nAChR genes and a mechanistic explanation for anthelmintic
tachyphylaxis.
3. Our approach in Aim #1 will be to characterize, molecularly and pharmacologically, the four
 or more nAChRs subtypes present on Brugia somatic muscle. In Aim #2, we will identify the
 functions of nAChR subunit genes by using RNAi on Brugia adults to produce different
 phenotypes and to alter muscle responses to different cholinergic anthelmintics. In Aim #3,
 we will test the hypothesis that populations of receptor subtypes are dynamic, compensating
 for the effects of anthelmintic exposure; we will determine how the L-subtype nAChRs
 behave during tachyphylaxis.
4. The proposal is innovative, using a combination of techniques for the study of functional
 properties of filarial nAChR ion-channels genes. To our knowledge, we are the only lab that
 has been able to combine these techniques successfully for the study of nematode parasites.
5. The overall impact, by an innovative combination of techniques, we will discover important
 new information on: ●the functional properties of filarial nAChR genes sensitive to
 anthelmintics; ●the dynamic nature of different receptor subtypes and; ●the loss of functional
 receptors and expression of genes associated with anthelmintic tachyphylaxis

## Key facts

- **NIH application ID:** 10129877
- **Project number:** 5R01AI047194-19
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Richard John Martin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2001-01-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129877

## Citation

> US National Institutes of Health, RePORTER application 10129877, Pharmacological Diversity of nAChRs in Clade III Nematodes: Brugia malayi (5R01AI047194-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129877. Licensed CC0.

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