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Article

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

Ferring Research Institute, Inc., Ferring Pharmaceuticals, San Diego, California (R.L.); and Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada (A.H., I.L.)

Abstract

I. Smooth Muscle Cell Ca2+ Handling and Role of the Sarcoplasmic Reticulum

A. Ca2+ Handling

B. Sarcoplasmic Reticulum

C. Capacitative Ca2+ Entry

D. Sarcoplasmic Reticulum Fractions and Interaction with Mitochondria

E. Ca2+ Storage by the Sarcoplasmic Reticulum

F. Estimates of Ca2+ Content in the Sarcoplasmic Reticulum

G. Ca2+ Uptake and Release by the Sarcoplasmic Reticulum

II. Physiological and Pharmacological Agents

A. Ca2+ Pump (Sarco/Endoplasmic Reticulum Ca2+-ATPase)

1. Thapsigargin.

2. Cyclopiazonic Acid.

3. 2,5-Di-(tert-butyl)-1,4-benzohydroquinone.

B. Ca2+-Gated Ca2+ Release Channel/Ryanodine Receptor

1. Cyclic ADP-Ribose and Analogs.

2. Caffeine and 9-Methyl-7-bromoeudistomin D.

3. Ryanodine.

4. Procaine.

5. Ruthenium Red.

C. Inositol 1,4,5-Triphospate-Gated Ca2+ Release Channel/Inositol 1,4,5-Triphospate Receptor

1. Inositol 1,4,5-Triphosphate.

2. Adenophostins.

3. Xestospongins.

4. 2-Aminoethoxy-Diphenylborate.

5. mAb18A10 and Other Neutralizing Anti-Inositol 1,4,5-Triphosphate Receptor Antibodies.

6. Heparin.

III. Conclusions and Perspectives

The sarco/endoplasmic reticulum (SR/ER) is the primary storage and release site of intracellular calcium (Ca²⁺) in many excitable cells. The SR is a tubular network, which in smooth muscle (SM) cells distributes close to cellular periphery (superficial SR) and in deeper aspects of the cell (deep SR). Recent attention has focused on the regulation of cell function by the superficial SR, which can act as a buffer and also as a regulator of membrane channels and transporters. Ca²⁺ is released from the SR via two types of ionic channels [ryanodine- and inositol 1,4,5-trisphosphate-gated], whereas accumulation from thecytoplasm occurs exclusively by an energy-dependent sarco-endoplasmic reticulum Ca²⁺-ATPase pump (SERCA). Within the SR, Ca²⁺ is bound to various storage proteins. Emerging evidence also suggests that the perinuclear portion of the SR may play an important role in nuclear transcription. In this review, we detail the pharmacology of agents that alter the functions of Ca²⁺ release channels and of SERCA. We describe their use and selectivity and indicate the concentrations used in investigating various SM preparations. Important aspects of cell regulation and excitation-contractile activity coupling in SM have been uncovered through the use of such activators and inhibitors of processes that determine SR function. Likewise, they were instrumental in the recent finding of an interaction of the SR with other cellular organelles such as mitochondria. Thus, an appreciation of the pharmacology and selectivity of agents that interfere with SR function in SM has greatly assisted in unveiling the multifaceted nature of the SR.

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