Modulation of calcium-sensitive potassium (BK) channels by oxygen is important in several mammalian tissues, and in the carotid body it is crucial to respiratory control. However, the identity of the oxygen sensor remains unknown. We demonstrate that hemoxygenase-2 (HO-2) is part of the BK channel complex and enhances channel activity in normoxia. Knockdown of HO-2 expression reduced channel activity, and carbon monoxide, a product of HO-2 activity, rescued this loss of function. Inhibition of BK channels by hypoxia was dependent on HO-2 expression and was augmented by HO-2 stimulation. Furthermore, carotid body cells demonstrated HO-2-dependent hypoxic BK channel inhibition, which indicates that HO-2 is an oxygen sensor that controls channel activity during oxygen deprivation.

The combination of studies in native tissues and immortalised model systems during the last decade has made possible a deeper understanding of the physiology and functional morphology of arterial and airway oxygen sensors. Complementary and overlapping information from these earlier studies has allowed a detailed description of the cellular events that link decreased environmental oxygen to the release of physiologically important vasoactive transmitters. Since these basic pathways have now been defined functionally, what remains to be determined is the molecular identity of the specific proteins involved in the signal transduction pathways, and how these proteins interact to produce a full physiological response. With these goals clearly in sight, we have embarked upon a strategy that is a novel combination of proteomics and functional genomics. It is hoped this strategy will enable us to develop and refine the initial models in order to understand more completely the process of oxygen sensing in health and disease. Anat Rec Part A 270A: 41-50, 2003.

No abstract

No abstract

No abstract