Targeted Disruption of Kir2.1 and Kir2.2 Genes Reveals the Essential Role of the Inwardly Rectifying K ⁺ Current in K ⁺ -Mediated Vasodilation

Abstract

The molecular bases of inwardly rectifying K(+) (Kir) currents and K(+)-induced dilations were examined in cerebral arteries of mice that lack the Kir2.1 and Kir2.2 genes. The complete absence of the open reading frame in animals homozygous for the targeted allele was confirmed. Kir2.1(-/-) animals die 8 to 12 hours after birth, apparently due to a complete cleft of the secondary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals. Voltage-dependent K(+) currents were similar in cells from neonatal control and Kir2.1(-/-) animals. An increase in the extracellular K(+) concentration from 6 to 15 mmol/L caused Ba(2+)-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animals did not dilate when the extracellular K(+) concentration was increased to 15 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries.

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen–Tawil syndrome

“…[11][12][13] The proper buffering and siphoning of extracellular potassium levels by the glia cells is instrumental for providing an electrochemical gradient for driving potassium into glia and thus regaining the propagation of neuronal action potential between the nodes of Ranvier. 14 Therefore, dysfunction of Kirs may lead to cell death and structure lesions in the CNS.…”

Functional Expression of Inward Rectifier Potassium Channels in Cultured Human Pulmonary Smooth Muscle Cells: Evidence for a Major Role of Kir2.4 Subunits

“…Genetic manipulation has been employed recently to further clarify the molecular nature of K IR channels and their function in smooth muscle. Using Kir2.1 and Kir2.2 knock-out mice, the presence of K IR currents was observed in cerebral artery smooth muscle cells isolated from control animals but were absent in myocytes from Kir2.1-/-animals (Zaritsky et al, 2000). In addition, the dilator response to K + was completely absent in Kir2.1-/-but not Kir2.2-/-animals, suggesting the functional importance of Kir2.1 (Zaritsky et al, 2000).…”

“…Using Kir2.1 and Kir2.2 knock-out mice, the presence of K IR currents was observed in cerebral artery smooth muscle cells isolated from control animals but were absent in myocytes from Kir2.1-/-animals (Zaritsky et al, 2000). In addition, the dilator response to K + was completely absent in Kir2.1-/-but not Kir2.2-/-animals, suggesting the functional importance of Kir2.1 (Zaritsky et al, 2000). Our data showing Ba 2+ (100 μM) to significantly depolarize the resting membrane potential in cultured HPASM cells suggests that K IR channels do indeed contribute to the resting membrane potential in these cells.…”

Cardiac ion channels

“…67 Kir2.1 deficient mice die shortly after birth; whereas Kir2.2¡/¡ mice are viable and display no gross abnormalities. 68,69 Potent blockers of Kir2 channels are rare. Weak, off-target Kir2 activity has been found in a few drugs, including the breast cancer drug tamoxifen, the anti-histamine diphenhydramine and the anti-malarial agent chloroquine.…”