Mitogens and Oncogenes Can Block the Induction of Specific Voltage-Gated Ion Channels

Abstract

The mechanisms underlying the ontogeny of voltage-gated ion channels in musde are unknown. Whether expression of voltage-gated channels is dependent on mitogen withdrawal and growth arrest, as is generally true for the induction of muscle-specific gene products, was investigated in the BC3H1 musde cell line by patch-clamp techniques. Differentiated BC3H1 myocytes expressed functional Ca2+ and Na+ channels that corresponded to those found in T tubules of skeletal muscle. However, Ca2" and Na+ channels were first detected after about 5 days of mitogen withdrawal.In order to test whether cellular oncogenes, as surrogates for exogenous growth factors, could prevent the expression of ion channels whose induction was contingent on mitogen withdrawal, BC3H1 cells were modified by stable transfection with oncogene expression vectors. Expression vectors containing v-erbB, or c-myc under the control of the SV40 promoter, delayed but did not prevent the appearance of functional Ca2" and Na+ channels. In contrast, transfection with a Val"2 c-H-ras vector, or cotransfection of c-myc together with v-erbB, suppressed the formation of functional Ca2' and Na+ channels for >4 weeks. Potassium channels were affected neither by mitogenic medium nor by transfected oncogenes. Thus, the selective effects of certain oncogenes on ion channel induction corresponded to the suppressive effects of mitogenic medium.

Sodium Channels: Clones and Consequences

“…These results broadly complement other findings showing that ion channel expression is altered during cancer progression (e.g. Caffrey et al 1987;Repp et al 1993).…”

Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels.

“…An additional important finding of this study is that after denervation for at least 24 (8,(20)(21)(22). Thus, innervation-induced events analogous to those occurring during normal maturation of neonatal myocytes is a unifying hypothesis that might explain many of these observations (23,24).…”

“…What signal might be produced by direct contact with the sympathetic nerve to produce increased expression of L-type calcium channels? Neurotransmitter(s) that induce differentiation (22,(25)(26)(27) or that might alter Gprotein expression (2,19,28) …”

Down-regulation of L-type Ca2+ Channel Transcript Levels by 1,25-Dihyroxyvitamin D3

“…With regard to plasma membrane Ca 2ϩ permeability, an obvious difference between osteoblasts and the excitable tissues is the total number of the functional VSCCs expressed. ROS 17/2.8 cells express between 1000 and 2000 functional L-type Ca 2ϩ channels per cell (5) while differentiated myocytes contain at least 10 times this level (31). This difference in VSCC levels is also apparent at the mRNA level, in which standard Northern blotting techniques used routinely for excitable tissues are frequently incapable of detecting low levels of VSCC mRNA in cells such as ROS 17/2.8.…”