Gene expression of prohormone and proprotein convertases in the rat CNS: a comparative in situ hybridization analysis

Abstract

Posttranslational processing of proproteins and prohormones is an essential step in the formation of bioactive peptides, which is of particular importance in the nervous system. Following a long search for the enzymes responsible for protein precursor cleavage, a family of Kexin/subtilisin-like convertases known as PC1, PC2, and furin have recently been characterized in mammalian species. Their presence in endocrine and neuroendocrine tissues has been demonstrated. This study examines the mRNA distribution of these convertases in the rat CNS and compares their expression with the previously characterized processing enzymes carboxypeptidase E (CPE) and peptidylglycine alpha-amidating monooxygenase (PAM) using in situ hybridization histochemistry. Furin mRNA was ubiquitously distributed and detected both in neurons and non-neuronal tissue throughout the brain with a higher abundance in ependyma, the circumventricular organs, the islands of Calleja, hippocampus, and allocortex. The cellular localization of PC1 and PC2 was exclusively neuronal with highest concentrations in known neuropeptide-rich brain regions. In general, PC2 was more widely expressed than PC1 in the CNS, although many regional variations were detected. The identification of specific combinations of convertase expression together with CPE and PAM expression in neuropeptide-rich brain regions suggests that specific enzymatic pathways are involved in neuropeptide precursor processing, and that these specific combinations are responsible for region-specific differences of posttranslational processing.

Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases

“…Seidah et al IFEBS Letters 379 (1996) study their possible coregulation [17]. For example, in the dentate gyrus of the hippocampus which expresses significant amounts of mRNAs coding for furin and PC1 [16] as well as PC7 [11] but not for PACE4 or PC5/6-B [28], the cognate processing enzymes may be reduced to the former two with the possible participation of PC1 in the processing of proBDNF (Fig. 4) [17].…”

“…Of the known convertases, only furin [10], PC5/6-B [12], a C-terminally extended isoform of PC5 [13] and possibly PC7 [11] contain a C-terminal transmembrane domain. Since all members of the convertase family can cleave precursors at the consensus type I cleavage site Arg-X-(Lys/Arg)-Argl [14], it became apparent that aside from cleavage specificity the cognate convertase(s) must also be correctly colocalized and possibly coregulated with their substrate within either the Trans Golgi Network (TGN) or in secretory granules [9,15,16]. Accordingly, studies on the colocalization of the neurotrophin mRNAs with those of the convertases and their coregulation revealed that more than one convertase can colocalize with the neurotrophins [17].…”

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…61,62 These enzymes are found in high concentrations in the pituitary gland and some brain regions. 63 Most of the endogenous peptides are secreted as inactive precursors and converted into an active form by PC1/3 and PC2. PC1/3 and PC2 response to opioid exposure appears to be biphasic.…”

Sorting and processing of secretory proteins

“…Furin [244,245], PACE 4 [212] and PC6A [213] are expressed in most tissues and cells so far analysed (albeit at different levels from one cell type to the next). PC6B is expressed mainly in intestine [214], and expression of PCI and PC2 is restricted to endocrine and neuroendocrine tissues [205,207] including the brain [246][247][248].…”

“…[205,209]. The mRNA distribution in the rat central nervous system has been studied very extensively by in situ hybridization [248]. PCI and PC2 were localized exclusively to neuronal cells, but PC2 was more widely expressed than PCI.…”