Biomedical Engineering Reference
In-Depth Information
sodium current activated on hyperpolarization of the cell membrane and is continued
and sustained by other currents [1]. The latter incorporate a balance between inward
currents carried by calcium and the sodium/calcium exchanger and outward currents
carried by potassium. Activation of the pacemaker potential is increased by
betaadrenergic catecholamines and reduced by acetylcholine through their respective
G protein-coupled receptors and the adenylyl cyclase-cyclic AMP second messenger
system via a cyclic AMP binding site near the carboxyl terminus of the channel.
g
Fig. 1.
The role of
I
f
in generation of pacemaker potentials in the sinoatrial node (SAN).
a
Pacemaker potentials in the SAN under control conditions, and after
ȕ
-adrenergic stimulation
with norepinephrine. The four major currents that control the generation of the pacemaker
potential are indicated:
I
f
[produced by hyperpolarization activated, cyclic nucleotide gated
(HCN) channels], T-type (
I
CaT
) and L-type (
I
CaL
) calcium currents, and repolarizing K currents
(
I
K
).
b
Scheme of an SAN cell showing the regulation of the HCN channel by up-or
downregulation of cellular cyclic adenosine monophosphate (cAMP).
M
2 type-2 muscarinic
receptor,
ACh
acetylcholine,
AC
adenylyl cyclase, GĮi G-protein Į subunit (inhibits AC),
GȕȖ
G-protein
ȕȖ
subunit,
ȕ
1-AR
ȕ
1-adrenergic receptor,
G
Įs G-protein a subunit (stimulates AC),
ǻV shift of the voltage dependence of HCN channel activation induced by increase or decrease
of cAMP (reprinted by permission from reference [1]).
We reasoned that overexpression of
I
f
in either secondary pacemaker tissues of the
cardiac specialized conducting system or in non-pacemaker cells of the myocardium
could provide a nidus of pacemaker activity to drive the heart in a ''demand'' mode in
