Are Caenorhabditis elegans receptors useful targets for drug discovery: Pharmacological comparison of tyramine receptors with high identity from C. elegans (TYRA-2) and Brugia malayi (Bm4)

Abstract

The biogenic amine, tyramine (TA), modulates a number of key processes in nematodes and a number of TA-specific receptors have been identified. In the present study we have identified a putative TA receptor (Bm4) in the recently completed Brugia malayi genome and compared its pharmacology to its putative C. elegans orthologue, TYRA-2, under identical expression and assay conditions. TYRA-2 and Bm4 are the most closely related C. elegans and B. malayi BA receptors and differ by only 14 aa in the TM regions directly involved in ligand binding. Membranes from HEK-293 cells stably expressing Bm4 exhibited specific, saturable, high-affinity, [ 3 H]LSD and [ 3 H]TA binding with K d s of 18.1 ± 0.93 nM and 15.1 ± 0.2 nM, respectively. More importantly, both TYRA-2 and Bm4 TA exhibited similar rank orders of potencies for a number of potential tyraminergic ligands. However, some significant differences were noted. For example, chloropromazine exhibited an order of magnitude higher affinity for Bm4 than TYRA-2 (pK i s of 7.6 ± 0.2 and 6.49 ± 0.1, respectively). In contrast, TYRA-2 had significantly higher affinity for phentolamine than Bm4. These results highlight the utility of the nearly completed B. malayi genome and the importance of using receptors from individual parasitic nematodes for drug discovery.

Anthelmintic effect of thymol and thymol acetate on sheep gastrointestinal nematodes and their toxicity in mice

“…This receptor modulates a number of key processes in nematodes, including pharyngeal pumping, locomotion and egg laying (SMITH et al, 2007), besides being expressed in all phases of the life cycle of H. contortus (RAO et al, 2010), justifying the possible interaction of this monoterpene with SER-2 tyramine receptor and its larvicidal action. Both thymol and TA showed larvicidal action indicating that replacement of the hydroxyl radical by the acetyl group did not change the larvicidal activity of TA, proving that the action of thymol is not related to the hydroxyl radical.…”

Molecular Characterization and Functional Analysis of a Putative Octopamine/Tyramine Receptor during the Developmental Stages of the Pacific Oyster, Crassostrea gigas

“…BLAST analysis against the NCBI non-redundant protein database (nr) revealed that CgGPR1 shows the most significant sequence identity with characterized LymOAR2 (42%) [22], the Caenorhabditis elegans TA receptor TYRA2 (32%) [36], and the Brugia malayi TA receptor Bm4 (29%) [37], suggesting that CgGPR1 is likely to be a biogenic amine receptor.…”

“…elegans TYRA2 [36] and B . malayi Bm4 [37]. Among these, CgGPR1 was phylogenetically most closely related to L .…”

“…malayi Bm4 on cAMP has not been studied, Bm4 may exhibit similar pharmacological characteristics as C . elegans TYRA2 owing to their high sequence identity (78%) [37]. CgGPR1, together with L .…”

Ion channels and receptor as targets for the control of parasitic nematodes

“…All of these molecules act at GPCRs (Komuniecki et al, 2004), though, as stated earlier, nematodes also possess chloride channels gated by 5-HT, dopamine and tyramine. At least some of these receptors have also been identified in parasitic species (Huang et al, 1999(Huang et al, , 2002Smith et al, 2003Smith et al, , 2007 and many have distinct pharmacological characteristics that suggest that nematode-specific agonists and antagonists could be developed as useful anthelmintics (White et al, 2007). In C. elegans, dopamine and 5-HT have well-established roles in modulating behavior, including locomotion, feeding and egg-laying (Chase and Koelle, 2007).…”