title: Postnatal development of transmural gradients in expression of ion channels and Ca²⁺-handling proteins in the ventricle.
abstract: Transmural gradients in myocyte action potential duration (APD) and Ca(2+)-handling proteins are argued to be important for both the normal functioning of the ventricle and arrhythmogenesis. In rabbit, the transmural gradient in APD (left ventricular wedge preparation) is minimal in the neonate. During postnatal development, APD increases both in the epicardium and the endocardium, but the prolongation is more substantial in the endocardium leading to a significant transmural gradient. We have investigated changes in the expression of ion channels and also Ca(2+)-handling proteins in the subepicardial and subendocardial layers of the left ventricular free wall in neonatal (2-7 days of age) and adult male (~6 months of age) New Zealand White rabbits using quantitative PCR and also, when possible, in situ hybridisation and immunohistochemistry. In the adult, there were significant and substantial transmural gradients in Ca(v)1.2, KChIP2, ERG, K(v)LQT1, K(ir)2.1, NCX1, SERCA2a and RyR2 at the mRNA and, in some cases, protein level-in every case the mRNA or protein was more abundant in the epicardium than the endocardium. Of the eight transmural gradients seen in the adult, only three were observed in the neonate and, in two of these cases, the gradients were smaller than those in the adult. However, in the neonate there were also transmural gradients not observed in the adult: in HCN4, Na(v)1.5, minK, K(ir)3.1 and Cx40 mRNAs - in every case the mRNA was more abundant in the endocardium than the epicardium. If the postnatal changes in ion channel mRNAs are used to predict changes in ionic conductances, mathematical modelling predicts the changes in APD observed experimentally. It is concluded that many of the well known transmural gradients in the ventricle develop postnatally.
authors.affiliation: Cardiovascular Medicine, Faculty of Medical and Human Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: Eman S H
authors.initials: ES
authors.lastname: Abd Allah
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Aslanidi
authors.forename: James O
authors.initials: JO
authors.lastname: Tellez
authors.forename: Joseph
authors.initials: J
authors.lastname: Yanni
authors.forename: Rudi
authors.initials: R
authors.lastname: Billeter
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Halina
authors.initials: H
authors.lastname: Dobrzynski
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D004699:Endocardium / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010496:Pericardium / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D054815:Cyclic Nucleotide-Gated Cation Channels; D051638:Ether-A-Go-Go Potassium Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D051657:KCNQ1 Potassium Channel; D051605:Kv Channel-Interacting Proteins; C419385:L-type calcium channel alpha(1C); D062554:NAV1.5 Voltage-Gated Sodium Channel; D019837:Ryanodine Receptor Calcium Release Channel; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases