<s>
In	O
the	O
pacemaking	B-Algorithm
cells	I-Algorithm
of	O
the	O
heart	O
(	O
e.g.	O
,	O
the	O
sinoatrial	O
node	O
)	O
,	O
the	O
pacemaker	B-Algorithm
potential	I-Algorithm
(	O
also	O
called	O
the	O
pacemaker	B-Algorithm
current	I-Algorithm
)	O
is	O
the	O
slow	O
,	O
positive	O
increase	O
in	O
voltage	O
across	O
the	O
cell	O
's	O
membrane	O
(	O
the	O
membrane	O
potential	O
)	O
that	O
occurs	O
between	O
the	O
end	O
of	O
one	O
action	B-Algorithm
potential	I-Algorithm
and	O
the	O
beginning	O
of	O
the	O
next	O
action	B-Algorithm
potential	I-Algorithm
.	O
</s>
<s>
This	O
increase	O
in	O
membrane	O
potential	O
is	O
what	O
causes	O
the	O
cell	O
membrane	O
,	O
which	O
typically	O
maintains	O
a	O
resting	O
membrane	O
potential	O
around	O
-65	O
mV	O
,	O
to	O
reach	O
the	O
threshold	B-Algorithm
potential	I-Algorithm
and	O
consequently	O
fire	O
the	O
next	O
action	B-Algorithm
potential	I-Algorithm
;	O
thus	O
,	O
the	O
pacemaker	B-Algorithm
potential	I-Algorithm
is	O
what	O
drives	O
the	O
self-generated	O
rhythmic	O
firing	O
(	O
automaticity	O
)	O
of	O
pacemaker	B-Algorithm
cells	I-Algorithm
,	O
and	O
the	O
rate	O
of	O
change	O
(	O
i.e.	O
,	O
the	O
slope	O
)	O
of	O
the	O
pacemaker	B-Algorithm
potential	I-Algorithm
is	O
what	O
determines	O
the	O
timing	O
of	O
the	O
next	O
action	B-Algorithm
potential	I-Algorithm
and	O
thus	O
the	O
intrinsic	O
firing	O
rate	O
of	O
the	O
cell	O
.	O
</s>
<s>
In	O
a	O
healthy	O
sinoatrial	O
node	O
(	O
SAN	O
,	O
a	O
complex	O
tissue	O
within	O
the	O
right	O
atrium	O
containing	O
pacemaker	B-Algorithm
cells	I-Algorithm
that	O
normally	O
determine	O
the	O
intrinsic	O
firing	O
rate	O
for	O
the	O
entire	O
heart	O
)	O
,	O
the	O
pacemaker	B-Algorithm
potential	I-Algorithm
is	O
the	O
main	O
determinant	O
of	O
the	O
heart	O
rate	O
.	O
</s>
<s>
Because	O
the	O
pacemaker	B-Algorithm
potential	I-Algorithm
represents	O
the	O
non-contracting	O
time	O
between	O
heart	O
beats	O
(	O
diastole	O
)	O
,	O
it	O
is	O
also	O
called	O
the	O
diastolic	B-Algorithm
depolarization	I-Algorithm
.	O
</s>
<s>
The	O
amount	O
of	O
net	O
inward	O
current	O
required	O
to	O
move	O
the	O
cell	O
membrane	O
potential	O
during	O
the	O
pacemaker	B-Device
phase	O
is	O
extremely	O
small	O
,	O
in	O
the	O
order	O
of	O
few	O
pAs	O
,	O
but	O
this	O
net	O
flux	O
arises	O
from	O
time	O
to	O
time	O
changing	O
contribution	O
of	O
several	O
currents	O
that	O
flow	O
with	O
different	O
voltage	O
and	O
time	O
dependence	O
.	O
</s>
<s>
Evidence	O
in	O
support	O
of	O
the	O
active	O
presence	O
of	O
K+	O
,	O
Ca2+	O
,	O
Na+	O
channels	O
and	O
Na+	O
/K	O
+	O
exchanger	O
during	O
the	O
pacemaker	B-Device
phase	O
have	O
been	O
variously	O
reported	O
in	O
the	O
literature	O
,	O
but	O
several	O
indications	O
point	O
to	O
the	O
“	O
funny	O
”	O
( If	O
)	O
current	O
as	O
one	O
of	O
the	O
most	O
important	O
.	O
</s>
<s>
(	O
see	O
funny	B-Algorithm
current	I-Algorithm
)	O
.	O
</s>
<s>
There	O
is	O
now	O
substantial	O
evidence	O
that	O
also	O
sarcoplasmic	O
reticulum	O
(	O
SR	O
)	O
Ca2+	O
-transients	O
participate	O
to	O
the	O
generation	O
of	O
the	O
diastolic	B-Algorithm
depolarization	I-Algorithm
via	O
a	O
process	O
involving	O
the	O
Na	O
–	O
Ca	O
exchanger	O
.	O
</s>
<s>
The	O
rhythmic	O
activity	O
of	O
some	O
neurons	O
like	O
the	O
pre-Bötzinger	O
complex	O
is	O
modulated	O
by	O
neurotransmitters	O
and	O
neuropeptides	O
,	O
and	O
such	O
modulatory	O
connectivity	O
gives	O
to	O
the	O
neurons	O
the	O
necessary	O
plasticity	O
to	O
generating	O
distinctive	O
,	O
state-dependent	O
rhythmic	O
patterns	O
that	O
depend	O
on	O
pacemaker	B-Algorithm
potentials	I-Algorithm
.	O
</s>
<s>
The	O
heart	O
has	O
several	O
pacemakers	B-Device
,	O
each	O
which	O
fires	O
at	O
its	O
own	O
intrinsic	O
rate	O
:	O
</s>
<s>
The	O
firing	O
of	O
the	O
pacemaker	B-Algorithm
cells	I-Algorithm
is	O
induced	O
electrically	O
by	O
reaching	O
the	O
threshold	B-Algorithm
potential	I-Algorithm
of	O
the	O
cell	O
membrane	O
.	O
</s>
<s>
The	O
threshold	B-Algorithm
potential	I-Algorithm
is	O
the	O
potential	O
an	O
excitable	O
cell	O
membrane	O
,	O
such	O
as	O
a	O
myocyte	O
,	O
must	O
reach	O
in	O
order	O
to	O
induce	O
an	O
action	B-Algorithm
potential	I-Algorithm
.	O
</s>
<s>
This	O
depolarization	O
is	O
caused	O
by	O
very	O
small	O
net	O
inward	O
currents	O
of	O
calcium	O
ions	O
across	O
the	O
cell	O
membrane	O
,	O
which	O
gives	O
rise	O
to	O
the	O
action	B-Algorithm
potential	I-Algorithm
.	O
</s>
<s>
Bio-pacemakers	O
are	O
the	O
outcome	O
of	O
a	O
rapidly	O
emerging	O
field	O
of	O
research	O
into	O
a	O
replacement	O
for	O
the	O
electronic	B-Device
pacemaker	I-Device
.	O
</s>
<s>
The	O
bio-pacemaker	O
turns	O
quiescent	O
myocardial	O
cells	O
(	O
e.g.	O
</s>
<s>
atrial	O
cells	O
)	O
into	O
pacemaker	B-Algorithm
cells	I-Algorithm
.	O
</s>
<s>
This	O
is	O
achieved	O
by	O
making	O
the	O
cells	O
express	O
a	O
gene	O
which	O
creates	O
a	O
pacemaker	B-Algorithm
current	I-Algorithm
.	O
</s>
