Expression spannungsabhängiger Hirntyp-Natriumkanäle im sich entwickelnden Myokard der Ratte

Expression spannungsabhängiger Hirntyp-Natriumkanäle im sich entwickelnden Myokard der Ratte

Differential expression of brain-type voltage gated sodium channels in the developing rat myocardium

Christian Thomas Alflen

Doctoral thesis

Date of Examination: 2013-11-06

Date of issue: 2013-11-05

Advisor: Paul, Thomas Prof. Dr.

Referee: Paul, Thomas Prof. Dr.

Referee: Sossalla, Samuel T. PD Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0001-BC24-9

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Abstract

English

Voltage gated sodium channels (VGSC) conduct the sodium current responsible for the rapid upstroke of the myocardial action potential. SCN5A is the VGSC mainly expressed in the heart. Mutations of SCN5A result in severe inherited cardiac arrhythmia syndromes, namely LQTS 3 and Brugada Syndrome. Recently, other subtypes of VGSC, predominantly expressed in neuronal tissue (brain-type VGSC), have been shown to exist in the adult myocardium and to play an important role in excitation contraction coupling as well as in normal sinuatrial node function. Alterations of brain-type VGSC function is known to result in distinct neurological disease like epilepsy syndromes or subtypes of migraine syndromes already in infancy and childhood. The aim of this study was to investigate the differential expression of brain-type VGSC (SCN1A, SCN8A) and heart specific SCN5A in the developing rat myocardium by means of rt-PCR and Western Blot analysis at developmental stage E17 (gestational age 17 days) antenatally and at the age of 1, 7 and 21 days as well as 6 weeks postnatally. Significant changes of VGSC expression in rat myocardium during ante- and postnatal development could be detected. Whereas SCN5A RNA levels increased after birth to maximum values on day 21, the highest SCN1A RNA levels were detected on day 1 - 7 and decreased thereafter. SCN8A RNA was maximally expressed during embryonic stage E17 and decreased after birth. At the protein level, different results were obtained. Whereas the amount of SCN5A protein increased along with the RNA level, SCN1A protein level decreased after birth in contrast to RNA expression. Western Blot could not detect SCN8A protein in the myocardium at any stage of development. The high expression level of SCN1A in the perinatal period and early infancy indicates its importance in preserving a regular cardiac rhythm in this early phase of life. Altered regulation of VGSC expression at either RNA- or protein level might result in severe cardiac rhythm disturbances.

Keywords: Voltage gated sodium channels; developing myocardium