Hippocampal cholinergic neurostimulating peptides (HCNP)

Neuronal development and differentiation require a variety of cell interact ions. Diffusible molecules from target neurons play an important part in me diating such interactions. Our early studies used explant culture technique to examine the factors that enhance the differentiation of septo-hippocamp al cholinergic neurons, and they revealed that several components resident in the hippocampus are involved in the differentiation of presynaptic choli nergic neurons in the medial septal nucleus. One of these components, originally purified from young rat hippocampus, is a novel undecapeptide (hippocampal cholinergic neurostimulating peptide; H CNP) this enhances the production of ChAT, but not of AchE. Later experiments revealed that: (1) a specific receptor appears to mediate this effect; (2) NGF and HCNP act cooperatively to regulate cholinergic ph enotype development in the medial septal nucleus in culture; and (3) these two molecules differ both in their mechanism of release from the hippocampu s and their mechanism of action on cholinergic neurons. The amino acid sequence deduced from base sequence analysis of cloned HCNP- precursor protein cDNA shows that HCNP is located at the N-terminal domain of its precursor protein. The 21 kDa HCNP precursor protein shows homology with other proteins, and i t functions not only as an HCNP precursor, but also as a binding protein fo r ATP, opioids and phosphatidylethanolamine. The distribution and localization of HCNP-related components and the expres sion of their mRNAs support the notion that the precursor protein is multif unctional. In keeping with its multiple functions, the multiple enhancers and promoter s found in the genomic DNA for HCNP precursor protein may be involved in th e regulation of its gene in a variety of cells and at different stages of d evelopment. Furthermore, several lines of evidence obtained from studies of humans and animal models suggest that certain types of memory and learning disorders ale associated with abnormal accumulation and expression of HCNP analogue peptide and/or its precursor protein mRNA in the hippocampus. (C) 1999 Elsevier Science Ltd. All rights reserved.