In spite of tremendous pharmaceutical interest in the details of interactions of regulatory peptides with their specific receptors on cell membranes, the details are still poorly understood. Data on binding of about a dozen of peptides to receptors embedded in dodecylphosphocholine micelles suggest that: (i) upon binding to its receptor a ligand may interact with the lipid bilayer around the receptor; (ii) interactions with cell membranes involve 4 to 12 amino acid residues of a peptide, which are included in 4 to 33 amino acids-long segments of its molecules, and only 4 to 5 amino acids-long motifs interact in the entirety with a membrane.
Non-receptor-mediated interactions are more common for short-chain regulatory peptides. By fitting to the major groove of DNA molecules (Fig. 1 N), a short peptide may influence the transcription of strictly defined genes (see Ch. 3), which makes one of the basic principles of the epigenetic regulation of physiological functions by peptides (Fig. 1 O). This mechanism will be considered in more detail in Ch. 3; however, generally it conforms to the following scheme :
CPPs → gene expression → protein synthesis → physiological changes, e.g. ageing
Although the physiological significance of peptide bonds is widely recognized, the role of peptides, especially short-chain ones, in the physiological regulation is underestimated. Regulation involving separate amino acids might be at work quite early in the evolution of prokaryotes. For example, the regulatory effects of amino acids of the proliferation of bacteria are known. With the advent of the peptide bond, there emerged the possibility to write down in a peptide molecule much more information to be conferred to a target cell. This provided for a more specific regulation of cell functions.
Regulatory peptides emerge largely by the enzymatic cleavage of their precursor proteins synthesized at ribosomes. For short-chain peptides, a non-ribosomal mechanism of their synthesis cannot be ruled out.
The main producers of regulatory peptides are the neurosecretory cells present in all organs, mainly in the intestine, endocrine glands and the brain. A part of peptides may emerge in gut lumen due of the cleavage of food-derived proteins and to synthesis, both ribosomal and non-ribosomal, by microbiota. It is also possible that regulatory peptides are formed in their target cells by virtue of the synthesis of precursor proteins and their subsequent enzymatic cleavage.
There exist dedicated systems for the active transport of regulatory peptides through biological barriers, including the intestinal wall, brain-blood barrier, and cellular and nuclear membranes. Regulatory peptides may enter their target cells using the same mechanism as that used by cell-penetrating peptides (CPPs).
The effects of long-chain regulatory peptides on their target cells are mediated largely by binding to specific receptors on the cell surface. Short-chain peptides may act in non-receptor ways – by penetrating into cells and nuclei, binding to DNA molecules and changing gene expression (these topic will be treated in more detail in Chapters 3 and 4).
Because of the ability of short-chain peptides to interact with DNA in a non-receptor-medicated manner, their role in the physiological regulation is much more significant than it has been being admitted so far.