Gene Therapy to Create Biological Pacemakers - Biopacemaking - page 80

depolarization or phase 4 depolarization. This phase 4 depolarization results in the
formation of action potentials, thereby triggering the contraction of the heart (Fig. 1a).
The most important current underlying this process is the ''funny current'' or I f .
A family of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is
believed to underlie this inward current. There are four HCN isoforms which are all
expressed in the heart, but expression levels vary among regions [30, 41]. In the rabbit
SA node, HCN4 is the dominant transcript representing more than 81% of total HCN

Fig. 1. a Potential changes in the SA node and some ion channels that are involved. The
process of slow diastolic depolarization is initiated by I f , which is activated upon
hyperpolarization. HCN channels are the main proteins underlying this current. When the
threshold is reached, the action potential starts as a result of the opening of T-type and L-type
calcium channels. Repolarization occurs mainly due to the opening of K +

currents. A faster rate
is shown by the effect of ȕ -adrenergic stimulation with norepinephrine (NE), and results from
the increase in the slope of phase 4 depolarization. b Regulation of HCN channel activity by
alterations of intracellular cyclic adenosine monophosphate (cAMP). ȕ 1 -Adrenergic receptor
( ȕ 1 -AR) stimulation increases cAMP levels, as a result of G-protein coupled regulation of
adenylyl cyclase (AC) activity. M 2 -muscarinic receptor stimulation results in the opposite.
Cyclic AMP binds to HCN channels near the amino terminus, where it accelerates activation
kinetics and shifts the voltage dependence of activation to more positive voltages (as shown on
top, see also Fig. 3) (from reference [2], with permission).