Prekallikrein (PK) is the precursor of the trypsin-like plasma protease kallikrein (PKa), which cleaves kininogens to release bradykinin and converts the protease precursor factor XII (FXII) to the enzyme FXIIa. PK and FXII undergo reciprocal conversion to their active forms (PKa and FXIIa) by a process that is accelerated by a variety of biological and artificial surfaces. The surface-mediated process is referred to as contact activation. Previously, we showed that FXII expresses a low level of proteolytic activity (independently of FXIIa) that may initiate reciprocal activation with PK. The current study was undertaken to determine whether PK expresses similar activity. Recombinant PK that cannot be converted to PKa was prepared by replacing Arg371 with alanine at the activation cleavage site (PK-R371A, or single-chain PK). Despite being constrained to the single-chain precursor form, PK-R371A cleaves high-molecular-weight kininogen (HK) to release bradykinin with a catalytic efficiency ∼1500-fold lower than that of kallikrein cleavage of HK. In the presence of a surface, PK-R371A converts FXII to FXIIa with a specific activity ∼4 orders of magnitude lower than for PKa cleavage of FXII. These results support the notion that activity intrinsic to PK and FXII can initiate reciprocal activation of FXII and PK in solution or on a surface. The findings are consistent with the hypothesis that the putative zymogens of many trypsin-like proteases are actually active proteases, explaining their capacity to undergo processes such as autoactivation and to initiate enzyme cascades.
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http://dx.doi.org/10.1182/blood.2019002224 | DOI Listing |
Front Physiol
December 2024
Biomedical Science Department, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Myocardial ischemia causes the production and release of metabolites such as bradykinin, which stimulates cardiac spinal sensory afferents, causing chest pain and an increase in sympathetic activity referred to as the cardiogenic sympathetic afferent reflex. While the brain stem nuclei, such as the nucleus tractus solitarius and rostral ventrolateral medulla, are essential in the cardiogenic sympathetic afferent reflex, the role of other supramedullary nuclei in the cardiogenic sympathetic afferent reflex are not clear. The dorsomedial hypothalamic nucleus (DMH) is involved in cardiovascular sympathetic regulation and plays an important role in the sympathetic response to stressful stimuli.
View Article and Find Full Text PDFCells
December 2024
Astria Pharmaceuticals, Boston, MA 02210, USA.
The plaques associated with Alzheimer's disease are formed as a result of the aggregation of Aβ peptides, which vary in length from 38 to 43 amino acids. The 1-40 peptide is the most abundant, while the 1-42 peptide appears to be the most destructive to neurons and/or glial cells in a variety of assays. We have demonstrated that aggregated Aβ, a state prior to plaque formation, will activate the plasma bradykinin-forming pathway when tested in vitro.
View Article and Find Full Text PDFJ Med Virol
January 2025
Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany.
Int J Mol Sci
December 2024
Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Communications between different cell types within a tissue are often critical for the proper functioning of an organ. In the central nervous system, interactions among neurons and glial cells are known to modulate neurotransmission, energy metabolism, extracellular ion homeostasis, and neuroprotection. Here we showed that bradykinin, a proinflammatory neuropeptide, can be detected by astrocytes, resulting in the secretion of cytokines that act on neurons.
View Article and Find Full Text PDFBMC Vet Res
December 2024
CIRALE, USC 957, BPLC, Ecole Nationale Vétérinaire d'Alfort, 94700, Maisons-Alfort, France.
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