Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 345

α s , inducing positive inotropy and lusitropy
via adenylate cyclase and protein kinase-A. Both

β 1-Adrenoceptors are coupled to G

β 2- and β 3-adrenoceptors activate

G α s ,G α i ,orG α q according to the humoral context. G α s and G α q protein sets work

with adenylate cyclase and PLC β pathways, respectively. Members of the G α i set

can act via G βγ .DimerG βγ activates phosphoinositol 3-kinase.

β 2-Adrenoceptors are preferentially coupled to G α s , but they also bind

G α i -orG α q -coupled receptors. When stimulated by noradrenaline, β 2-

adrenoceptors interact much faster with G α s than with G α i or G α q . Besides,

PKA-dependent phosphorylation of β 2-adrenoceptors switches the G-coupling

from G α s to G α i , thus inhibiting ACase and activating the MAPK cascade.

3-Adrenoceptors lack phosphorylation sites. They thus are not desensitized
by GRKs, PKA, or PKC kinase. Adrenoceptors-

β

3exist
postsynaptically in cardiomyocytes, smooth myocytes, and endothelial cells.

α 1-, - α 2, and - β 1to β

β -

Adrenoceptors are major regulators of the cardiac activity.
Positive inotropic and lusitropic effects of 2-adrenoceptors are

mediated by PKA phosphorylation of phospholamban, troponin-I, Ca V 1 channel,
and ryanodine receptor RyR2. Cardiac phosphodiesterases degrade cAMP, thus
limiting the magnitude of

β 1- and β

-adrenoceptor stimulation. At least 4 phosphodiesterase
types (PDE1-PDE4), mostly in the cell cortex, exist in cardiomyocytes. 83
Positive chronotropy can be achieved by shifting the activation curve of the ion
channels to more positive voltages. Such a process is used by cAMP and cGMP to
increase HCN channel activity. Cyclic nucleotides bind to HCN channels. The HCN
channels are activated during membrane hyperpolarization after the termination of
an action potential and yield Na + influx, which slowly depolarizes the sarcolemma.
Several types of voltage-gated HCN cation channels exist (HCN1-HCN4). Isotype
HCN4 is the predominant type in the sinoatrial node. Sympathetic stimulation of
the sinoatrial node raises cAMP concentrations, hence accelerating depolarization
and the cardiac frequency. Stimulation of muscarinic receptors slows the heart rate
by an inverse action.

β

signal transmission rate. Elevated intracellular calcium levels during sustained activity inhibit
adenylate cyclases ACase5 and ACase6.
83 Activity of PDE1 depends on the calcium-calmodulin complex, the quantity of which increases
concomitantly with elevation in cytoplasmic calcium level. Subtype PDE2 is stimulated by cAMP
messenger. Subtype PDE3 is inhibited by cAMP agent. Subtype PDE4 is insensitive to cAMP
mediator.