Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 388

Tabl e 8. 4. Main features of IP 3 R isoforms (Source: [ 717 ]). In vascular smooth myocytes, IP 3 R
receptors localize to the central sarco(endo)plasmic reticulum around the nucleus as well as its
peripheral region beneath the plasma membrane. They thus can regulate Ca 2 + -dependent gene
expression as well as local signaling to membrane proteins. IP 3 R channel is activated at a cytosolic
Ca 2 + level 300 nmol; an elevation in cytosolic Ca 2 + level together with calmodulin inhibit IP 3 R

channel. Agent ATP is not required for IP 3 R activation, but enhances sensitivity to IP 3 and Ca 2 +
ligands. Binding of IP 3 to IP 3 R in aortic and tracheal smooth myocytes is weak at pH

<

7and
maximal at pH ranging from 8 to 9. In portal vein smooth myocytes, a pH increase from 6.7
to 7.0-7.3 reduces the Ca 2 + concentration required for IP 3 R activation. Reactive oxygen species
stimulate IP 3 R-mediated Ca 2 + release in aorta smooth myocytes, whereas they impede SERCA
pump in coronary artery smooth myocytes, but do not affect IP 3 R activity in mesenteric artery
smooth myocytes.

<

IP 3 R1 IP 3 R2 IP 3 R3

IP 3 affinity Intermediate Highest Lowest

( ∼ 270 nmol) ( ∼ 100 nmol) ( ∼ 400 nmol)

Activation by Ca 2 +

∼ 170 nmol ∼ 150 nmol ∼ 60 nmol

Inhibition by Ca 2 +

∼ ∼ ∼

370 nmol 160 nmol 170 nmol

Sensitivity to ATP High None Low

( ∼ 130 mol) ( ∼ 2 mmol)

Influence of pH 6.8 7.5

(IP 3 binding,
Ca 2 + sensitivity)

Alternative splicing Yes None described None described

Density of IP 3 Rs results from the balance between gene transcription and
protein degradation. Transcription factor MyB binds to the Ip 3 r1 promoter and
stimulates transcription, whereas retinoic acid precludes it via Activator protein-
2[ 717 ]. Hydrogen peroxide promotes proteasomal degradation of IP 3 R1 and
IP 3 R3, whereas JaK2 kinase phosphorylates IP 3 R1 and prevents its proteasomal
degradation. Vasopressin impedes IP 3 R1 gene transcription and favors protein
degradation [ 717 ].
Several ligands (IP 3 , cytosolic and sarco(endo)plasmic reticulum luminal Ca 2 + ,
and ATP), kinases (inhibitory PKA and PKG and stimulatory PKC and Tyr kinases),
and other types of regulators (FKBP12 via inhibitory PP3 and stimulatory TOR,
scaffold enhancer RACK1) and modulators (cellular pH 16 and reactive oxygen

species) control IP 3 R activity [ 717 ].
In addition, IP 3 R communicates with adjoining ryanodine-sensitive Ca 2 + chan-
nels of the sarco(endo)plasmic reticulum as well as mitochondria to influence Ca 2 +
release from its main store as well as reactive oxygen species generation. It can
couple to plasmalemmal transient receptor potential channels (e.g., TRPC1 and

16 Cellular pH influences IP 3 binding to IP 3 R and sensitivity of IP 3 RtoCa 2 + ion.