Biomedical Sciences Publications Biomedical Sciences 10-2005 Neuropeptide signalling systems in flatworms P. McVeigh Queen's University Belfast M. J. Kimber Iowa State University, [email protected] E. Novozhilova Iowa State University T. A. Day Iowa State University, [email protected] Follow this and additional works at: http://lib.dr.iastate.edu/bms_pubs Part of the Parasitology Commons The ompc lete bibliographic information for this item can be found at http://lib.dr.iastate.edu/ bms_pubs/21. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Biomedical Sciences at Iowa State University Digital Repository. It has been accepted for inclusion in Biomedical Sciences Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Neuropeptide signalling systems in flatworms Abstract Two distinct families of neuropeptides are known to endow platyhelminth nervous systems – the FMRFamide-like peptides (FLPs) and the neuropeptide Fs (NPFs). Flatworm FLPs are structurally simple, each 4–6 amino acids in length with a carboxy terminal aromatic-hydrophobic-Arg-Phe-amide motif. Thus far, four distinct flatworm FLPs have been characterized, with only one of these from a parasite. They ah ve a widespread distribution within the central and peripheral nervous system of every flatworm examined, including neurones serving the attachment organs, the somatic musculature and the reproductive system. The only physiological role that has been identified for flatworm FLPs is myoexcitation. Flatworm NPFs are believed to be invertebrate homologues of the vertebrate neuropeptide Y (NPY) family of peptides. Flatworm NPFs are 36–39 amino acids in length and are characterized by a caboxy terminal GRPRFamide signature and conserved tyrosine residues at positions 10 and 17 from the carboxy terminal. Like FLPs, NPF occurs throughout flatworm nervous systems, although less is known about its biological role. While there is some evidence for a myoexcitatory action in cestodes and flukes, more compelling physiological data indicate that flatworm NPF inhibits cAMP levels in a manner that is characteristic of NPY action in vertebrates. The widespread expression of these neuropeptides in flatworm parasites highlights the potential of these signalling systems to yield new targets for novel anthelmintics. Although platyhelminth FLP and NPF receptors await identification, other molecules that play pivotal roles in neuropeptide signalling have been uncovered. These enzymes, involved in the biosynthesis and processing of flatworm neuropeptides, have recently been described and offer other distinct and attractive targets for therapeutic interference. Keywords Platyhelminthes, Trematode, Cestode, Turbellarian, Planarian, FMRFamide, Neuropeptide F, Prohormone convertase, Amidation Disciplines Parasitology Comments This article is from Parasitology 131 (2005): S41–S55, doi:10.1017/S0031182005008851. Posted with permission. This article is available at Iowa State University Digital Repository: http://lib.dr.iastate.edu/bms_pubs/21 S41 Neuropeptide signalling systems in flatworms P. MCVEIGH1, M. J. KIMBER2, E. NOVOZHILOVA2 and T. A. DAY 2* 1 Parasitology Research Group, Queen’s University Belfast, Belfast BT9 7BL, Northern Ireland, UK 2 Department of Biomedical Sciences, Iowa State University, Ames IA 50011, USA SUMMARY Two distinct families of neuropeptides are known to endow platyhelminth nervous systems – the FMRFamide-like peptides (FLPs) and the neuropeptide Fs (NPFs). Flatworm FLPs are structurally simple, each 4–6 amino acids in length with a carboxy terminal aromatic-hydrophobic-Arg-Phe-amide motif. Thus far, four distinct flatworm FLPs have been characterized, with only one of these from a parasite. They have a widespread distribution within the central and peripheral nervous system of every flatworm examined, including neurones serving the attachment organs, the somatic musculature and the reproductive system. The only physiological role that has been identified for flatworm FLPs is myoexcitation. Flatworm NPFs are believed to be invertebrate homologues of the vertebrate neuropeptide Y (NPY) family of peptides. Flatworm NPFs are 36–39 amino acids in length and are characterized by a caboxy terminal GRPRFamide signature and conserved tyrosine residues at positions 10 and 17 from the carboxy terminal. Like FLPs, NPF occurs throughout flatworm nervous systems, although less is known about its biological role. While there is some evidence for a myoexcitatory action in cestodes and flukes, more compelling physiological data indicate that flatworm NPF inhibits cAMP levels in a manner that is characteristic of NPY action in vertebrates. The widespread expression of these neuropeptides in flatworm parasites highlights the potential of these signalling systems to yield new targets for novel anthelmintics. Although platyhelminth FLP and NPF receptors await identification, other molecules that play pivotal roles in neuropeptide signalling have been uncovered. These enzymes, involved in the biosynthesis and processing of flatworm neuropeptides, have recently been described and offer other distinct and attractive targets for therapeutic interference. Key words: Platyhelminthes, trematode, cestode, turbellarian, planarian, FMRFamide, neuropeptide F, prohormone convertase, amidation. INTRODUCTION stage, there are reasons to believe that neuropep- tidergic systems could yield novel drug targets for a Investigations of the functional neuromuscular bi- whole new generation of anthelmintic drugs. ology of parasitic platyhelminths historically focused There is clear evidence that neuropeptides are on small molecule, classical neurotransmitters such central to the biology of flatworms and, as illus- as acetylcholine, serotonin and catecholamines. The tration, neuropeptide immunostaining outstrips that excitatory action of serotonin and the inhibitory reported for classical transmitter molecules in flat- action of acetylcholine (ACh) on fluke muscle prep- worms (Halton & Maule, 2004). Two distinct classes arations was described over 50 years ago (Chance & of neuropeptides have been identified within the Mansour, 1953). These systems have provided tar- phylum. Firstly, there are FMRFamide-like pep- gets for anthelmintic drugs; for example, cholinergic tides (FLPs), which are relatively short peptides agonists have been used to treat tapeworm infections. (typically 20 amino acids) ending in a carboxy- In comparison, it was only recently that the < terminal RFamide motif. Secondly, there are neuro- importance of neuropeptides in platyhelminths has peptide Fs (NPFs), which are larger peptides (36–40 been recognised by parasitologists. The previous amino acids) that are related to the vertebrate chapter of this supplement (Ribiero, El-Shehabi & neuropeptide Y (NPY) family of peptides. Patocka, in this supplement) exposes some of the In addition to playing a central role in flatworms, impediments to the study of flatworm neuro- the importance of neuropeptides in nematodes has muscular biology. Add to these the relatively recent also become apparent. One inaccurate concept is that awareness of the biological importance of neuro- the two phyla of worms are very similar, such that peptides in the phylum, and the understanding of the things learned from the nematodes can be easily ex- neuromuscular role of flatworm neuropeptides is trapolated to the platyhleminths. The other extreme truly in its nascency. However, even at this early would also be inaccurate – that is, to think that the worms are completely dissimilar such that there will be no commonalities between the two phyla. This * Corresponding author: Department of Biomedical Sciences, Iowa State University, Ames IA 50011, USA. principle can be illustrated in the context of a Tel: +515-294-7100. Fax: +515-294-7100. E-mail: quick overview of platyhemlinth neuropeptides in [email protected] comparison to nematode neuropeptides. Parasitology (2005), 131, S41–S55. f 2005 Cambridge University Press doi:10.1017/S0031182005008851 Printed in the United Kingdom P. McVeigh and others S42 The most easily noted disparity between the two Table 1. FMRFamide-like (FLPs) biochemically phyla is the dramatic disproportion in the breadth of identified from platyhelminths neuropeptides expressed by worms from the two groups. Each nematode species has a staggering Species Sequence Reference complement of apparent neuropeptides, with at least Moniezia expansa GNFFRF Maule et al. 1993b 236 distinct peptides encoded in the genome of amide C. elegans and 67 of these being FLPs (Li, Kim & Arthurdendyus RYIRF amide Maule et al. 1994 Nelson, 1999; Pierce et al. 2001; Kim & Li, 2004; triangulatus McVeigh et al. 2005). This wide neuropeptide Girardia tigrina GYIRF amide Johnston et al. 1995b complement is apparent in parasitic nematodes as Bdelloura candida GYIRF amide Johnston et al. 1996 Bdelloura candida YIRF amide Johnston et al. 1996 well, where biochemical and genetic information has confirmed at least 27 distinct FLPs in Ascaris suum (Davis & Stretton, 1996; Yew et al. 2005). Compared high picomolar range (Day et al. 1997; Humphries to this staggering complement of FLPs present in et al. 2004). typical free-living and parasitic species of nematodes, This paper will provide an overview of what is only one or two distinct FLPs have been found in known about the role of neuropeptides in