Molecular control of pacemaking and conduction Flashcards
Main function of AVN
Retard impulse propagation so atria contract before ventricles
Difference in membrane potential of pacemaker cells/AV node cells to myocyte cells
no resting membrane potentials - The moment that there is hyperpolarization after the end of the AP reached, the next AP will be generated rapidly by the opening of specific ion channels - HCN channels
Why is AP slower to uprise is nodes
Absence/weak expression of Na⁺ channels in node cells
Difference in plateau of atria vs ventricle
strongly present in ventricular myocyte but much less present in atria. Reflects that pumping work of ventricle has a longer time constant relative to the more stretch like capacity of the atria.
Which cardiac tissue has greatest AP amplitude?
Purkinje fibre network
Which type of cell does primitive heart AP represent?
Pacemaker
Which genes cause conversion of myocytes to fast pump acting myocutes and expression of Na channels and proliferation
Tbx5 and Tbx20
Which genes important for Nodal cells
• A number of transcription factors collectively supress expression of Nkx2.5 and other transcription factors to repress chamber myocardium differentiation
• Tbx3: supresses expression of chamber myocardium genes
• Tbx18: supresses expression of Connexin 43
Shox2: supresses expression of Nkx2.5
Which genes important for atrial cells?
Nkx2.5 (and Tbx5)
• Both have a stimulatory role for chamber myocardium genes
• Suppresses expression of Tbx3 and HCN4 (ion channel specifically expressed in SAN, particularly active during the pacemaker potential)
Which gene stops SAN developing in left atrium?
Pitx2 - blocks Nkx2.5
Location of SAN
border between caval vein and the right atrium
Who discovered SAN and when?
Arthur Keith and Martin Flack in 1906
Histological appearance of SAN
Node is consisting mainly of connective tissue (which allows nodal cells to be electrically isolated from surrounding chamber myocardium)
What is the crista terminalis
specific bundle of cardiomyocytes in the RA, which initially receive the electrical signal from the SAN
Molecular characteristics of SAN
absence of Nav1.5 and Cx43 expression.
○ Na⁺ channel expressed in chamber myocardial cells - channel is absent in SAN
HCN4 is abundantly expressed in the SAN (channel activated upon hyperpolarization)
Gradient of expression/transitional cells
Note: gradient of expression seen
There is a change from pure SAN to a mixed character in the transitional zone connecting the node with the chamber myocardium
Amplitude difference between SAN and ventricular myocytes
SAN: small
V: large
Upstroke velocity difference between SAN and ventricular myocytes
SAN: slow
V: fast
Funny current difference between SAN and ventricular myocytes
SAN: present
V: absent
Na channel difference between SAN and ventricular myocytes
SAN: absent
V: present
Gap junction difference between SAN and ventricular myocytes
SAN: sparse and slow
V: abundant and fast
Funny current channel in pacemaker cells
HCN4
Connexin responsible for gap junctions
Cx43
Clock mechanism
–> The oscillatory activity of the SAN is driven by two interlinked mechanisms: the Ca²⁺ clock and the membrane clock
RyR release of Ca²⁺ from the SR, leads to an ↑Ca²⁺ concentration in the cytoplasm
SR function is to restore Ca²⁺ levels using SERCA (taking Ca²⁺ from cytoplasm to back into the SR)
Uptake and release → Ca²⁺ oscillation SERCA plays an important role in pacemaking
Any Ca²⁺ present in the cytoplasm can modulate the ion channels in the membrane. In particular:
Ca/Na⁺ exchangers move Ca²⁺ out in exchange for Na⁺ in
High Ca²⁺ concentration in cytoplasm, leads to inward movement of Na⁺, and transport of Ca²⁺ outside Inward flowing Na⁺ is determined by the amount of Ca²⁺ released by the cytoplasm – the Na2 current produced is believed to be important with regards to cardiac pacemaking
