Aplysia allatotropin-related peptide and its newly identified d-amino acid–containing epimer both activate a receptor and a neuronal target

Abstract

l- to d-residue isomerization is a post-translational modification (PTM) present in neuropeptides, peptide hormones, and peptide toxins from several animals. In most cases, the d-residue is critical for the biological function of the resulting d-amino acid-containing peptide (DAACP). Here, we provide an example in native neuropeptides in which the DAACP and its all-l-amino acid epimer are both active at their newly identified receptor and at a neuronal target associated with feeding behavior. On the basis of sequence similarity to a known DAACP from cone snail venom, we hypothesized that allatotropin-related peptide (ATRP), a neuropeptide from the neuroscience model organism, may form multiple diastereomers in the central nervous system. We determined that ATRP exists as a d-amino acid-containing peptide (d2-ATRP) and identified a specific G protein-coupled receptor as an ATRP receptor. Interestingly, unlike many previously reported DAACPs and their all-l-residue analogs, both l-ATRP and d2-ATRP were potent agonists of this receptor and active in electrophysiological experiments. Finally, d2-ATRP was much more stable than its all-l-residue counterpart in plasma, suggesting that in the case of ATRP, the primary role of the l- to d-residue isomerization may be to protect this peptide from aminopeptidase activity in the extracellular space. Our results indicate that l- to d-residue isomerization can occur even in an all-l-residue peptide with a known biological activity and that in some cases, this PTM may help modulate peptide signal lifetime in the extracellular space rather than activity at the cognate receptor.

Functional studies on neuropeptides and receptors in model animal <italic>Aplysia</italic>

“…Bai 等通过生物信息学比较，并采用多种质谱方法，在海兔摄食环路中识别了一个促进反刍运 动程序的含 D-型氨基酸神经肽，而且其 L-型差向异构体完全没有活性 [35] 。这项研究是第一次 在一个清晰的神经环路中发现含 D-型氨基酸神经肽的功能。Livnat 等进一步开发了一种系列 检测方法，这种方法可以在组织或细胞中没有偏好性地识别含 D-型氨基酸神经肽 [36] 。Checco 等 [37] 首次系统地研究了含 D-型氨基酸神经肽及其衍生物对其受体 [38] 在神经环路中的作用。有 趣的是，Checco 等的另一项研究 [23] 还发现，先前已证明有生物活性的 ATRP [25] 也存在含 D-型 Aplysia SCP (small cardioactive peptide)…”

“…程可能不同 [18] 。( 3)神经肽翻译后修饰的多样性。神经肽前体产生的同一个神经肽，经过不 同的蛋白翻译后修饰过程 (post-translational modifications， PTMs) ， 可能具有不同的生物活性。 大多数神经肽都需要经过 PTMs，常见的 PTMs 包括酰胺化 [19] ，糖基化，磷酸化，二硫键的形 成 [20,21] 以及神经肽中一个特定氨基酸从 L-型变为 D-型(即含 D-型氨基酸神经肽) [22,23] 等(图…”

Identification of an allatostatin C signaling system in mollusc Aplysia

“…We have examined allatostatin C function in an experimentally-advantageous system, the gastropod mollusc Aplysia californica . Aplysia has provided fundamental insight into the neural basis of motivated behaviors 17 – 33 , learning and memory 34 – 38 and neuromodulation 39 – 42 , including neuropeptides 43 – 52 and receptors 10 , 53 , 54 . In this work, we provide the first evidence for the presence of an AstC signaling system in molluscs.…”

Vibrational circular dichroism of d‐amino acid‐containing peptide NdWFamide in the crystal form

“…3,4 In fact, several neuropeptides, such as acatin, fulicin, fulyal, GdYFD, and allatotropin-related peptide (ATRP), are DAACPs that include D-amino acid residues at the second position. [5][6][7][8] Moreover, dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH 2 ), which is isolated from the skin secretions of Phyllomedusa sauvagei, is the first DAACP derived from frogs. Its biological activity is about 1000 times greater than that of morphine.…”

“…To date, more than 50 types of DAACPs have been reported, where those possessing d ‐amino acids at the second position from the N‐terminal exhibit specific bioactivity 3,4 . In fact, several neuropeptides, such as acatin, fulicin, fulyal, GdYFD, and allatotropin‐related peptide (ATRP), are DAACPs that include d ‐amino acid residues at the second position 5–8 . Moreover, dermorphin (Tyr‐ d ‐Ala‐Phe‐Gly‐Tyr‐Pro‐Ser‐NH 2 ), which is isolated from the skin secretions of Phyllomedusa sauvagei , is the first DAACP derived from frogs.…”