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Cnidarians are the lowest animal group having a nervous system and it was probably within this phylum or in a related ancestor group that nervous systems first evolved. The primitive nervous systems of cnidarians are strongly peptidergic. From a single sea anemone species, Anthopleura elegantissima, 17 different neuropeptides have been isolated so far, and we expect that many more neuropeptides (more than 30) must be present. All peptides are localized in neurons of cnidarians and we have demonstrated the presence of some of the peptides in neurosecretory dense-cored vesicles. Most neuropeptides have an excitatory or inhibitory action on whole cnidarians, muscle preparations, and isolated muscle cells, suggesting that these peptides are neurotransmitters or neuromodulators. One neuropeptide induces metamorphosis in planula larvae to become a polyp. This shows that cnidarian neuropeptides also are involved in developmental processes, such as cell differentiation and pattern formation. We have cloned the preprohormones for most of the cnidarian neuropeptides. These preprohormones have a high copy number of the immature neuropeptide sequence, which can be up to 37 neuropeptide copies per precursor molecule. In addition to well-known, "classical" processing enzymes, novel prohormone processing enzymes must be present in cnidarian neurons. These include a processing enzyme hydrolyzing at the C-terminal sides of acidic (Asp and Glu) residues and a dipeptidyl aminopeptidase digesting at the C-terminal sides of N-terminally located X-Pro and X-Ala sequences. All this shows that the primitive nervous systems of cnidarians are already quite complex, and that neuropeptides play a central role in the physiology of these animals.

Using a radioimmunoassay against the C-terminal sequence Arg-Pro-NH2 (RPamide) we have isolated the neuropeptide

Using a radioimmunoassay against the C-terminal sequence Arg-Pro-NH2 (RPamide), we have isolated the peptide Leu-Pro-Pro-Gly-Pro-Leu-Pro-Arg-Pro-NH2 (Antho-RPamide) from an extract of the sea anemone Anthopleura elegantissima. Antho-RPamide is located in neurons of sea anemones. Application of low concentrations of Antho-RPamide to tentacle preparations of sea anemones strongly increased the frequency and duration of spontaneous contractions, suggesting that this peptide is involved in neurotransmission. Antho-RPamide has a free N-terminus, yet its X-Pro-Pro sequence makes it relatively resistant to degradation by nonspecific aminopeptidases. Thus, we have discovered another strategy by which sea anemones protect the N-termini of their bioactive neuropeptides.