<s>
The	O
pacemaker	B-Algorithm
current	I-Algorithm
(	O
If	O
,	O
or	O
IKf	O
,	O
also	O
called	O
funny	B-Algorithm
current	I-Algorithm
)	O
is	O
an	O
electric	O
current	O
in	O
the	O
heart	O
that	O
flows	O
through	O
the	O
HCN	O
channel	O
or	O
pacemaker	B-Device
channel	O
.	O
</s>
<s>
Such	O
channels	O
are	O
important	O
parts	O
of	O
the	O
electrical	B-Algorithm
conduction	I-Algorithm
system	I-Algorithm
of	I-Algorithm
the	I-Algorithm
heart	I-Algorithm
and	O
form	O
a	O
component	O
of	O
the	O
natural	B-Algorithm
pacemaker	I-Algorithm
.	O
</s>
<s>
First	O
described	O
in	O
the	O
late	O
1970s	O
in	O
Purkinje	B-Algorithm
fibers	I-Algorithm
and	O
sinoatrial	O
myocytes	O
,	O
the	O
cardiac	B-Algorithm
pacemaker	I-Algorithm
"	O
funny	O
"	O
(	O
If	O
)	O
current	O
has	O
been	O
extensively	O
characterized	O
and	O
its	O
role	O
in	O
cardiac	O
pacemaking	O
has	O
been	O
investigated	O
.	O
</s>
<s>
The	O
funny	B-Algorithm
current	I-Algorithm
is	O
highly	O
expressed	O
in	O
spontaneously	O
active	O
cardiac	O
regions	O
,	O
such	O
as	O
the	O
sinoatrial	O
node	O
(	O
SAN	O
,	O
the	O
natural	B-Algorithm
pacemaker	I-Algorithm
region	O
)	O
,	O
the	O
atrioventricular	O
node	O
(	O
AVN	O
)	O
and	O
the	O
Purkinje	B-Algorithm
fibres	I-Algorithm
of	O
conduction	B-Algorithm
tissue	O
.	O
</s>
<s>
The	O
funny	B-Algorithm
current	I-Algorithm
is	O
a	O
mixed	O
sodium	O
–	O
potassium	O
current	O
that	O
activates	O
upon	O
hyperpolarization	O
at	O
voltages	O
in	O
the	O
diastolic	O
range	O
(	O
normally	O
from	O
−	O
60/	O
−70	O
mV	O
to	O
−40	O
mV	O
)	O
.	O
</s>
<s>
When	O
,	O
at	O
the	O
end	O
of	O
a	O
sinoatrial	O
action	O
potential	O
,	O
the	O
membrane	O
repolarizes	O
below	O
the	O
If	O
threshold	O
(	O
about	O
−	O
40/	O
−50	O
mV	O
)	O
,	O
the	O
funny	B-Algorithm
current	I-Algorithm
is	O
activated	O
and	O
supplies	O
inward	O
current	O
,	O
which	O
is	O
responsible	O
for	O
starting	O
the	O
diastolic	B-Algorithm
depolarization	I-Algorithm
phase	O
(	O
DD	O
)	O
;	O
by	O
this	O
mechanism	O
,	O
the	O
funny	B-Algorithm
current	I-Algorithm
controls	O
the	O
rate	O
of	O
spontaneous	O
activity	O
of	O
sinoatrial	O
myocytes	O
,	O
and	O
thus	O
the	O
cardiac	O
rate	O
.	O
</s>
<s>
The	O
molecular	O
determinants	O
of	O
the	O
pacemaker	B-Algorithm
current	I-Algorithm
belong	O
to	O
the	O
HCN	O
channel	O
(	O
hyperpolarization-activated	O
cyclic	O
nucleotide	O
–	O
gated	O
channel	O
)	O
,	O
of	O
which	O
4	O
isoforms	O
(	O
HCN1	O
to	O
HCN4	O
)	O
are	O
known	O
.	O
</s>
<s>
Because	O
of	O
their	O
relevance	O
to	O
generation	O
of	O
pacemaker	B-Device
activity	O
and	O
modulation	O
of	O
spontaneous	O
frequency	O
,	O
f-channels	O
are	O
natural	O
targets	O
of	O
drugs	O
aimed	O
to	O
pharmacologically	O
control	O
heart	O
rate	O
.	O
</s>
<s>
Recent	O
studies	O
have	O
also	O
indicated	O
that	O
funny	B-Algorithm
channel	I-Algorithm
inhibition	O
can	O
be	O
used	O
to	O
reduce	O
the	O
incidence	O
of	O
coronary	O
artery	O
disease	O
outcomes	O
in	O
a	O
subgroup	O
of	O
patients	O
with	O
heart	O
rate	O
≥70	O
bpm	O
.	O
</s>
<s>
For	O
example	O
,	O
an	O
inherited	O
mutation	O
of	O
a	O
highly	O
conserved	O
residue	O
in	O
the	O
CNBD	O
of	O
the	O
HCN4	O
protein	O
(	O
S672R	O
)	O
is	O
associated	O
with	O
inherited	O
sinus	B-Algorithm
bradycardia	I-Algorithm
.	O
</s>
<s>
Biological	O
pacemakers	B-Device
,	O
generally	O
intended	O
as	O
cell	O
substrates	O
able	O
to	O
induce	O
spontaneous	O
activity	O
in	O
silent	O
tissue	O
,	O
represent	O
a	O
potential	O
tool	O
to	O
overcome	O
the	O
limitations	O
of	O
electronic	B-Device
pacemakers	I-Device
.	O
</s>
<s>
One	O
of	O
the	O
strategies	O
used	O
to	O
generate	O
biological	O
pacemakers	B-Device
involves	O
the	O
use	O
of	O
cells	O
inherently	O
expressing	O
or	O
engineered	O
to	O
express	O
funny	B-Algorithm
channels	I-Algorithm
.	O
</s>
