PMID- 12814325
OWN - NLM
STAT- MEDLINE
DCOM- 20040227
LR  - 20191107
IS  - 1175-2203 (Print)
IS  - 1175-2203 (Linking)
VI  - 3
IP  - 3
DP  - 2003
TI  - Mutations in cardiac sodium channels: clinical implications.
PG  - 173-9
AB  - Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins 
      responsible for the rapid action potential upstroke in most excitable cells. 
      Recently discovered mutations in VGSCs, which underlie idiopathic clinical 
      disease, have emphasized the importance of these channels in tissues such as 
      skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding 
      the cardiac sodium channel isoform (SCN5A) have been linked to at least three 
      abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada's 
      syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations in 
      SCN5A manifest as one or more of these clinical phenotypes - the precise 
      distinction between these diseases is increasingly subtle. Clinical management of 
      LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven 
      promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show 
      more sensitivity to flecainide than wild-type (WT) channels, while lidocaine 
      sensitivity is unchanged. One plausible explanation for differential drug 
      sensitivity is that mutant channels may allow more access to a receptor site 
      compared with WT through altered protein allosteric changes during an action 
      potential. The high affinity binding site for local anesthetic block has been 
      identified in the pore region of the channel. This region is not water accessible 
      during the closed state, thus requiring channel opening for charged drug 
      (flecainide and mexiletine) access and block. Channel mutations which disrupt 
      inactivation biophysics lead to increased drug binding by altering the time the 
      binding site is accessible during an action potential. Neutral drugs (lidocaine) 
      which are not dependent on channel opening for binding site access will not be 
      sensitive to mutations that alter channel inactivation properties. Interestingly 
      another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, 
      suggesting that although drug effects of SCN5A mutations cross disease 
      boundaries, clinical management with flecainide will be beneficial to patients in 
      a mutation-specific manner.
FAU - Liu, Huajun
AU  - Liu H
AD  - Department of Pharmacology, College of Physicians and Surgeons, Columbia 
      University, New York, New York 10032, USA.
FAU - Clancy, Colleen
AU  - Clancy C
FAU - Cormier, Joseph
AU  - Cormier J
FAU - Kass, Robert
AU  - Kass R
LA  - eng
GR  - 1P01-HL 67849-02/HL/NHLBI NIH HHS/United States
GR  - 1R01-HL-56810-5/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - New Zealand
TA  - Am J Pharmacogenomics
JT  - American journal of pharmacogenomics : genomics-related research in drug 
      development and clinical practice
JID - 100967746
RN  - 0 (Muscle Proteins)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (SCN5A protein, human)
RN  - 0 (Sodium Channel Blockers)
RN  - 0 (Sodium Channels)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Heart Diseases/drug therapy/*genetics
MH  - Humans
MH  - Muscle Proteins/antagonists & inhibitors/*genetics
MH  - Mutation/drug effects/*genetics
MH  - NAV1.5 Voltage-Gated Sodium Channel
MH  - Sodium Channel Blockers/pharmacology/therapeutic use
MH  - Sodium Channels/*genetics
RF  - 75
EDAT- 2003/06/20 05:00
MHDA- 2004/02/28 05:00
CRDT- 2003/06/20 05:00
PHST- 2003/06/20 05:00 [pubmed]
PHST- 2004/02/28 05:00 [medline]
PHST- 2003/06/20 05:00 [entrez]
AID - 333 [pii]
AID - 10.2165/00129785-200303030-00003 [doi]
PST - ppublish
SO  - Am J Pharmacogenomics. 2003;3(3):173-9. doi: 10.2165/00129785-200303030-00003.