Targeted replacement of Kv1.5 in the mouse leads to loss of the 4-aminopyridine-sensitive component of I-K,I-slow and resistance to drug-induced QT prolongation
B. London et al., Targeted replacement of Kv1.5 in the mouse leads to loss of the 4-aminopyridine-sensitive component of I-K,I-slow and resistance to drug-induced QT prolongation, CIRCUL RES, 88(9), 2001, pp. 940-946
The K+ channel mKv1.5 is thought to encode a 4-aminopyridine (4-AP)-sensiti
ve component of the current I-K,I-slow in the mouse heart. We used gene tar
geting to replace mKv1.5 with the 4-AP-insensitive channel rKv1.1 (SWAP mic
e) and directly test the role of Kv1.5 in the mouse ventricle. Kv1.5 RNA an
d protein wore undetectable, rKv1.1 was expressed, and Kv2.1 protein was up
regulated in homozygous SWAP hearts, The density of the K+ current I-K,I-sl
ow (depolarizations to +40 mV, pA/pF) was similar in left ventricular myocy
tes isolated from SWAP homozygotes (17 +/-1, n=27) and littermate controls
(16 +/-2, n=19), The densities and properties of I-peak, I-to,I-f, I-to,I-s
, and I-ss were also unchanged. In homozygous SWAP myocytes, the 50-mu mol/
L 4-AP-sensitive component of I-K,I-slow was absent (n=6), the density of T
he 20-mmol/L tetraethylammonium-sensitive component of I-K,I-slow was incre
ased (9 +/-1 versus, 5 +/-1, P <0.05), and no 100- to 200-nmol/L alpha -den
drotoxin-sensitive current was found (n=8). APD(90) in SWAP myocytes was si
milar to controls at baseline but did not prolong in response to 30 mu mol/
L 4-AP. Similarly, QTc (ms) was not prolonged in anesthetized SWAP mice (64
+/-2, homozygotes, n=9; 62 +/-2, controls, n=9)? and injection with 4-AP p
rolonged QTc only in controls (63 +/-1, homozygotes; 72 +/-2, controls, P <
0.05). SWAP mice had no increase in arrhythmias during ambulatory telemetry
monitoring. Thus, Kv1.5 encodes the 4-AP--sensitive component of I-K,I-slo
w in the mouse ventricle and confers sensitivity to 4-AP-induced prolongati
on of APD and QTc, Compensatory upregulation of Kv2.1 may explain the pheno
typic differences between SWAP mice and the previously described transgenic
mice expressing a truncated dominant-negative Kv1.1 construct.