1. Neuromodulation by multiple related peptides with different spectra of physiological effects appears an effective way to integrate complex physiological functions. A good opportunity to examine this issue occurs in the accessory radula closer (ARC) neuromuscular circuit of Aplysia, where, extensive previous work has shown, acetylcholine-induced contractions of the muscle are variously modulated by several families of peptide cotransmitters released under appropriate behavioral circumstances from the muscle's own two motor neurons. 2. In this work we focused on the myomodulins (MMs) released from motor neuron B16. Previous work has characterized MM(A) (PMSMLRLamide) and MM(B) (GSYRMMRLamide). We now similarly purified from ARC neuromuscular material and sequenced MM(C) (GWSMLRLamide), MM(D) (GLSMLRLamide), MM(E) (GLQMLRtamide), and MM(F) (SLNMLRLamide). Three additional MMs, MM(G) (TLSMLRLamide), MM(H) (GLHMLRamide), and MM(I) (SLSMLRLamide), are encoded by a known MM gene. B16 probably synthesizes, and coreleases, all nine MMs. Further MMs have been found in other mollusks. All evidence indicates that the MMs are a major, widely distributed family of molluscan neuropeptides important as neuromuscular modulators and probably also central transmitters or modulators. 3. MM effects on motor neuron B 16-elicited ARC muscle contractions were best analyzed as the sum of three distinct actions: potentiation, depression of the amplitude of the contractions, and acceleration of their relaxation rate. We compared the effectiveness of all nine MMs in these respects. We correlated this with their effectiveness in enhancing the L-type Ca current and activating a specific K current in voltage-clamped dissociated ARC muscle fibers, effects we previously proposed to underlie, respectively, the potentiation and the depression of contractions. 4. All nine MMs were similarly effective in enhancing the Ca current and, as far as it was possible to determine, potentiating the amplitude as well as accelerating the relaxation rate of the contractions. 5. In contrast, the MMs' ability to activate the K current and depress the contractions varied greatly. MM(B) and MM(C), in particular, were weak, whereas the other seven MMs were considerably more effective in both respects. 6. Altogether, we were able to explain the potentiating and depressing strengths of the MMs by the magnitude of their modulation of the Ca and K currents, providing further support for our hypothesis that the effects on contraction amplitude are mediated by the effects on the two currents. 7. The net effect on contraction amplitude was determined by the balance between the potentiation and depression. Although most MM concentrations had both potentiating and depressing actions, potentiated contractions predominated at low and depressed contractions (but with accelerated relaxation rate) at high concentrations. At 10 nM, all nine MMs increased net contraction amplitude by 50-150%; at 1-10 mu M, MM(B) and MM(C) continued to produce net potentiation but the other seven MMs completely abolished contractions. 8. Combined application of the MMs in proportions likely to be released in vive modulated the contractions no differently from the most common individual MM. We discuss the possibility that I some of the MM forms may be redundant in this system. 9. Functionally, the potentiation of contractions most likely helps strengthen feeding movements to meet behavioral demands, and the acceleration of the relaxation rate, perhaps together with the depression, may serve to limit the duration of the contractions so as to permit fast, energetically favorable switching between contractions of antagonistic muscles.
