53
3.4.5 Conclusion
In the retina, HCN channels appear to be necessary for the retinas temporal response to
light stimuli. Blocking them reduces its ability to respond to quickly changing light stimuli
[49, 48]. Although HCN expression is not limited to the photoreceptors [83], our results
suggest that their role in photoreceptors can explain in part the loss of the retinas temporal
resolution with HCN block. Changes in the rod and cone responses to flash, chirped, and
GWN light stimuli with HCN block all show a significant slowing of the response kinetics.
In light of these observations, it also makes sense that HCNl, the fastest of the four HCN
isoforms, is dominant in these cells. Incidentally, we also find that HCN activation does
not appear to be affected by background light, which is consistent with the very low cyclic
nucleotide sensitivity reported for the HCNl isoform [15].
In addition to elucidating how HCN channels function in photoreceptors, our study also
sheds light on our understanding of the visual side effects of a new class of heart medica-
tions that target cardiac HCN channels to slow heart rate [24, 99]. The visual side effects
of these drugs come from their action on HCN channels in the retina, which may well be
due to blocking HCN channels in photoreceptors. Our work, which shows that HCN1 is the
dominant isoform in rod and cone photoreceptors, suggests that newer cardiac drugs may
be able to minimize visμal side effects by selectively blocking HCN2 and 4, the cardiac HCN
isoforms [24]. A newly developed HCN blocker, ivabradine, appears to exhibit some thera-
peutic properties in this direction, and may lead the way for a shift in treatment of patients
with heart disease to more specific bradycardie agents [46,45].