The bradykinin-forming cascade: a historical perspective.

Area of Science:

• Biochemistry
• Physiology
• Molecular Biology

Background:

• Bradykinin formation in plasma is a complex cascade initiated by coagulation factor XII (Hageman factor), prekallikrein, and high-molecular-weight kininogen (HK).
• Prekallikrein and HK typically circulate as a stable bimolecular complex, with cascade initiation dependent on factor XII autoactivation and feedback loops.

Purpose of the Study:

• To review key discoveries over 50 years regarding the constituents and activation mechanisms of the plasma bradykinin-forming cascade.
• To highlight recent findings on prekallikrein's independent enzymatic activity and novel activation pathways.

Main Methods:

• Literature review of historical and recent research on the bradykinin cascade.
• Analysis of protein interactions and enzymatic activities involved in bradykinin release.

Main Results:

• Prekallikrein possesses intrinsic enzymatic activity, enabling it to cleave HK and liberate bradykinin, a function usually inhibited by C1 inhibitor.
• Heat shock protein 90 (HSP-90) and phosphate ions can trigger prekallikrein activation to kallikrein within the prekallikrein-HK complex, even without factor XII.
• These factors (HSP-90 and phosphate) can act additively, facilitating kallikrein generation prior to factor XII activation.

Conclusions:

• The plasma bradykinin cascade has more complex activation mechanisms than previously understood, involving factor XII-independent pathways.
• Prekallikrein's inherent enzymatic potential, modulated by interactions with HK and external factors like HSP-90, plays a crucial role in bradykinin formation.
• Understanding these diverse activation routes is essential for comprehending the physiological and pathological roles of the bradykinin system.