RELEASE CHANNEL ISOFORMS AND LOCAL CALCIUM SIGNALING

Project Details

Description

DESCRIPTION: (Applicant's Abstract)
The ryanodine receptor (Ryr, Ca2+ release channel) plays a central role in
muscle contraction. It is mainly localized where the sarcoplasmic reticulum
(SR) forms junctions with T-tubular and surface membranes (T-SR junction). It
is responsible for release of Ca2+ from SR that triggers contraction. Release
channels are suggested to be activated by two different mechanisms: mechanical
interaction with dihydropyridine receptor (DHPr, voltage sensor) and
calcium-induced calcium release (CICR).

Skeletal muscle contains different Ryr isoforms that might contribute to the
diversity of excitation-contraction coupling (ECC) mechanisms. My preliminary
data disclosed two distinctive types of local Ca2+ signaling: Ca2+ sparks and
release in small events. The goal of this proposal is to investigate the role
of different release channel isoforms in Ca2+ release. I propose to take
advantage of the fact that relative amounts of two major skeletal muscle Ryr
isoforms (Ryrl and Ryr3) vary widely between muscle types and during muscle
development in order to test three major hypotheses:

1. Ca2+ release in small events is directly controlled by voltage and provides
a precursor Ca2+ that activates Ca2+ sparks.

2. Ca2+ sparks are produced by opening of multiple Ryr Ca2+ release channels.

3. Ryr3rs are the channels required to produce sparks in skeletal muscle and
are activated by CICR.

For this we will explore local calcium signaling in a variety of mature and
developing mammalian, amphibian and fish skeletal muscle fibers with different
Ryr isoforms composition and/or different numbers of Ryrs per T-SR junction. In
parallel, we will monitor tissue expression of different Ryr isoforms by
immunoblotting and/or immunostaining.

Some muscle illnesses are increasingly been understood in terms of defects of
molecules participating in ECC. Proposed studies will greatly advanced our
knowledge of their functioning, which in turn could improve our understanding
of their role in decease.
StatusFinished
Effective start/end date8/1/997/31/06

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $180,155.00
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $200,479.00
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $192,084.00
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $182,451.00

ASJC

  • Signal Processing
  • Biochemistry

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