Abstract
Evolutionary origin and physiological significance of the tetrodotoxin (TTX) resistance of the vertebrate cardiac Na+ current (INa) is still unresolved. To this end, TTX sensitivity of the cardiac INa was examined in cardiac myocytes of a cyclostome (lamprey), three teleost fishes (crucian carp, burbot and rainbow trout), a clawed frog, a snake (viper) and a bird (quail). In lamprey, teleost fishes, frog and bird the cardiac INa was highly TTX-sensitive with EC50-values between 1.4 and 6.6 nmol·L−1. In the snake heart, about 80% of the INa was TTX-resistant with EC50 value of 0.65 μmol·L−1, the rest being TTX-sensitive (EC50 = 0.5 nmol·L−1). Although TTX-resistance of the cardiac INa appears to be limited to mammals and reptiles, the presence of TTX-resistant isoform of Na+ channel in the lamprey heart suggest an early evolutionary origin of the TTX-resistance, perhaps in the common ancestor of all vertebrates.
Highlights
Opening of the voltage-sensitive Na+ channels (Nav) depolarizes plasma membrane and causes a rapid impulse spread in excitable cells via abrupt Na+ influx
There were little differences in TTX sensitivity of INa among the fishes and the frog; in all species INa was highly sensitive to TTX with EC50-values between 1.4 (L. fluviatilis) and 6.6 nmol·L−1 (X. laevis)
When these values are compared to the EC50 value of the mammalian cardiac INa (1 μmol·L−1), the INa of the ectotherms is 2–3 orders of magnitude more sensitive than the
Summary
Opening of the voltage-sensitive Na+ channels (Nav) depolarizes plasma membrane and causes a rapid impulse spread in excitable cells via abrupt Na+ influx. The family of Nav channels consists of. 9 α-subunits in mammals and 8 α-subunits in teleost fish, which arose from 4 ancestral genes of early vertebrates through individual gene duplications and whole genome duplication (3R), respectively [1,2,3,4,5]. On the basis of their affinity to guanidium compounds tetrodotoxin (TTX) and saxitoxin (STX), Nav are classified into TTX-sensitive or TTX-resistant phenotypes. TTX-resistance is achieved by a mutation of an aromatic amino acid (tyrosine, Mar. Drugs 2011, 9 phenylalanine, tryptophan) in the position 401 (sequence numbering as in rat Nav1.4) to serine, cysteine or asparagine [6,7,8]. Other amino acid substitutions in various sites of the Na+
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