# STRUCTURE AND FUNCTION OF SARCOPLASMIC RETICULUM

> **NIH NIH R01** · BOSTON BIOMEDICAL RESEARCH INSTITUTE · 1993 · $421,122

## Abstract

One of the most important unsolved questions in muscle physiology is a
detailed understanding of the following sequential events:  (i)
depolarization of the transverse tubular system (T-tubule), (ii) Ca2+
release from sarcoplasmic reticulum (SR) leading to contraction, (iii)
reaccumulation of the released Ca2+ by the SR Ca2+ pump leading to
relaxation.  Our long range goal is to resolve each of these processes at a
molecular level in normal and diseased muscles.  Our current working
hypothesis is as follows.  The excitation signal elicited in the T-tubule
is transmitted via the dihydropyridine (DHP) receptor, probably with the
aid of several other proteins, to the foot protein (FP).  This leads to
conformational changes in the FP, and in turn activates the Ca2+ channel
located in FP.  The signal is further transmitted to a protein in the SR
lumen calsequestrin (CSQ), dissociating the bound calcium from CSQ.  The
dissociated Ca2+, which will eventually be released to the cytoplasm
through the activated channel, activates the Ca2+ pump leading to a prompt
reaccumulation of the released Ca2+.  Our specific aims are to resolve
individual steps of the hypothetical chain reactions using the isolated
triads capable of physiological excitation-contraction coupling, purified
protein components, and the reconstituted system.  Various steps involved
in the DHP receptor-mediated signal transmission pathway will be resolved
by using chemical antagonists and antibodies.  Involvement of other
proteins in the T-tubule - SR communication will also be examined by using
antibodies (and Fab subfragments) directed against them, and by
reconstitution experiments.  Conformational changes in the FP induced by
various effectors of Ca2+ release, especially the conformational changes
induced by the T-tubule depolarization, will be investigated using the
fluorescent probe incorporated into various domains of the FP moiety in a
site-directed fashion.  The question regarding the FP - CSQ communication
will be investigated by correlating conformational changes of FP and CSQ,
and dissociation of the CSQ-bound calcium during Ca2+ release reaction.  To
test the hypothesis that CSQ controls SR Ca2+ release, the kinetics of the
transient increase in the lumenal Ca2+ and the subsequent Ca2+ release from
SR will be correlated.  Kinetic behavior of the SR Ca2+ pump during Ca2+
release will be followed to examine reactivation of Ca2+ pumping and the
postulated role of CSQ in the reactivation process.

## Key facts

- **NIH application ID:** 3154924
- **Project number:** 5R01AR016922-20
- **Recipient organization:** BOSTON BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** NORIAKI IKEMOTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $421,122
- **Award type:** 5
- **Project period:** 1976-06-01 → 1996-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3154924

## Citation

> US National Institutes of Health, RePORTER application 3154924, STRUCTURE AND FUNCTION OF SARCOPLASMIC RETICULUM (5R01AR016922-20). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3154924. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*