Hemopressin and other bioactive peptides from cytosolic proteins: are these non-classical neuropeptides?

Abstract

Peptides perform many roles in cell-cell signaling; examples include neuropeptides, hormones, and growth factors. Although the vast majority of known neuropeptides are produced in the secretory pathway, a number of bioactive peptides are derived from cytosolic proteins. For example, the hemopressins are a family of peptides derived from alpha and beta hemoglobin which bind to the CB1 cannabinoid receptor, functioning as agonists or antagonists/inverse agonists depending on the size of the peptide. However, the finding that peptides derived from cytosolic proteins can affect receptors does not prove that these peptides are true endogenous signaling molecules. In order for the hemopressins and other peptides derived from cytosolic proteins to be considered neuropeptide-like signaling molecules, they must be synthesized in brain, they must be secreted in levels sufficient to produce effects, and either their synthesis or secretion should be regulated. If these criteria are met, we propose the name "non-classical neuropeptide" for this category of cytosolic bioactive peptide. This would be analogous to the non-classical neurotransmitters, such as nitric oxide and anandamide, which are not stored in secretory vesicles and released upon stimulation but are synthesized upon stimulation and constitutively released. We review some examples of cytosolic peptides from various protein precursors, describe potential mechanisms of their biosynthesis and secretion, and discuss the possibility that these peptides are signaling molecules in the brain, focusing on the criteria that these peptides would have to fill in order to be considered non-classical neuropeptides.

Fig. 1

Schematic of classical and non-classical neurotransmitters and neuropeptides. Top panel Classical neurotransmitters are typically synthesized in the presynaptic cell and packaged into synaptic vesicles. Upon stimulation, vesicles fuse with the membrane and release the neurotransmitters into the synaptic cleft where the neurotransmitters can bind to postsynaptic receptors to elicit their effects. Neurotransmitters in the synaptic cleft are removed by reuptake or are degraded. Classical neuropeptides are derived from precursors synthesized in the rough endoplasmic reticulum (ER). Proteolytic processing begins in the trans-Golgi network or immature secretory vesicles and continues in the maturing vesicles. Classical neuropeptides are packaged into dense core vesicles, which can also contain classical neurotransmitters. Upon stimulation, vesicles fuse with the membrane to release their contents. Classical neuropeptides typically elicit their effects on G-protein coupled receptors and are eliminated by extracellular peptidases. Bottom panel Non-classical neurotransmitters and the proposed pathway of non-classical neuropeptides. Non-classical neurotransmitters are synthesized from their precursors upon stimulation of the signaling cell and are not stored in vesicles. Examples such as anandamide and 2-arachidonoylglycerol are derived from lipid precursors while nitric oxide is produced from arginine. Once produced, non-classical neurotransmitters are rapidly secreted and act upon receptors or other targets which can be membrane-bound or intracellular. Non-classical signaling can proceed in a retrograde manner as it does not require synaptic transmission. In our proposed model, non-classical neuropeptides are derived from intracellular proteins by the action of proteases. The peptides are then secreted by an unknown mechanism, and elicit their effects on receptors or other targets. Although some of these targets may be distinct from the targets of classical neurotransmitters, some may also be common. For example, the hemopressins, a family of putative non-classical neuropeptides, bind to CB1 receptors which are also the target of the non-classical neurotransmitters anandamide and 2-arachidonoylglycerol

Fig. 2

Summary of the key properties of classical and non-classical neurotransmitters and neuropeptides. Examples of molecules in each category are listed