Oxygen sensitivity of cloned voltage-gated K(+) channels expressed in the pulmonary vasculature.
Hypoxic pulmonary vasoconstriction is initiated by inhibiting one or more voltage-gated potassium (Kv) channel in the vascular smooth muscle cells (VSMCs) of the small pulmonary resistance vessels. Although progress has been made in identifying which Kv channel proteins are expressed in pulmonary arterial (PA) VSMCs, there are conflicting reports regarding which channels contribute to the native O(2)-sensitive K(+) current. In this study, we examined the effects of hypoxia on the Kv1.2, Kv1.5, Kv2.1, and Kv9.3 alpha subunits expressed in mouse L cells using the whole-cell patch-clamp technique. Hypoxia (PO(2)= approximately 30 mm Hg) reversibly inhibited Kv1.2 and Kv2.1 currents only at potentials more positive than 30 mV. In contrast, hypoxia did not alter Kv1.5 current. Currents generated by coexpression of Kv2.1 with Kv9.3 alpha subunits were reversibly inhibited by hypoxia in the voltage range of the resting membrane potential (E(M)) of PA VSMCs ( approximately 28% at -40 mV). Coexpression of Kv1.2 and Kv1.5 alpha subunits produced currents that displayed kinetic and pharmacological properties distinct from Kv1.2 and Kv1.5 channels expressed alone. Moreover, hypoxia reversibly inhibited Kv1.2/Kv1.5 current activated at physiologically relevant membrane potentials ( approximately 65% at -40 mV). These results indicate that (1) hypoxia reversibly inhibits Kv1.2 and Kv2.1 but not Kv1.5 homomeric channels, (2) Kv1.2 and 1.5 alpha subunits can assemble to form an O(2)-sensitive heteromeric channel, and (3) only Kv1.2/Kv1.5 and Kv2.1/Kv9.3 heteromeric channels are inhibited by hypoxia in the voltage range of the PA VSMC E(M). Thus, these heteromeric channels are strong candidates for the K(+) channel isoforms initiating hypoxic pulmonary vasoconstriction.
Hulme
J T
JT
Department of Physiology, Colorado State University, Ft. Collins, CO 80523, USA.
Coppock
E A
EA
Felipe
A
A
Martens
J R
JR
Tamkun
M M
MM
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D010100:Oxygen / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats
D015221:Potassium Channels; D020033:Protein Isoforms; D010100:Oxygen