Changes underlying arrhythmia in the transgenic heart overexpressing Refsum disease gene-associated protein.
Previously, we identified a novel neuron-specific protein (PAHX-AP1) that binds to Refsum disease gene product (PAHX), and we developed transgenic (TG) mice that overexpress heart-targeted PAHX-AP1. These mice have atrial tachycardia and increased susceptibility to aconitine-induced arrhythmia. This study was undertaken to elucidate the possible changes in ion channels underlying the susceptibility to arrhythmia in these mice. RT-PCR analyses revealed that the cardiac expression of adrenergic beta(1)-receptor (ADRB1) was markedly lower, whereas voltage-gated potassium channel expression (Kv2.1) was higher in PAHX-AP1 TG mice compared with non-TG mice. However, the expression of voltage-sensitive sodium and calcium channels, and muscarinic receptor was not significantly different. Propranolol pretreatment, a non-specific beta-adrenoceptor antagonist, blocked aconitine-induced arrhythmia in non-TG mice, but not in PAHX-AP1 TG mice. Our results indicate that, in the PAHX-AP1 TG heart, the modulation of voltage-gated potassium channel and ADRB1 expression seem to be important in the electrophysiological changes associated with altered ion channel functions, but ADRB1 is not involved in the greater susceptibility to aconitine-induced arrhythmia.
Koh
Jeong Tae
JT
Dental Science Research Institute, Chonnam National University, Kwangju 501-190, Republic of Korea.
Jeong
Byung Chul
BC
Kim
Jae Ha
JH
Ahn
Young Keun
YK
Lee
Hyang Sim
HS
Baik
Yung Hong
YH
Kim
Kyung Keun
KK
D000157:Aconitine / Q000633:toxicity; D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis*; D011433:Propranolol / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis*; D011976:Receptors, Muscarinic / Q000096:biosynthesis; D012035:Refsum Disease / Q000235:genetics
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D009419:Nerve Tissue Proteins; C429045:Phyhip protein, mouse; D024642:Potassium Channels, Voltage-Gated; D018342:Receptors, Adrenergic, beta-1; D011976:Receptors, Muscarinic; D011433:Propranolol; D000157:Aconitine