PMID- 23077345
OWN - NLM
STAT- MEDLINE
DCOM- 20130620
LR  - 20211021
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 26
IP  - 12
DP  - 2012 Dec
TI  - Calcium signaling regulates trafficking of familial hypocalciuric hypercalcemia 
      (FHH) mutants of the calcium sensing receptor.
PG  - 2081-91
LID - 10.1210/me.2012-1232 [doi]
AB  - Calcium-sensing receptors (CaSRs) regulate systemic Ca(2+) homeostasis. 
      Loss-of-function mutations cause familial benign hypocalciuric hypercalcemia 
      (FHH) or neonatal severe hyperparathyroidism (NSHPT). FHH/NSHPT mutations can 
      reduce trafficking of CaSRs to the plasma membrane. CaSR signaling is potentiated 
      by agonist-driven anterograde CaSR trafficking, leading to a new steady state 
      level of plasma membrane CaSR, which is maintained, with minimal functional 
      desensitization, as long as extracellular Ca(2+) is elevated. This requirement 
      for CaSR signaling to drive CaSR trafficking to the plasma membrane led us to 
      reconsider the mechanism(s) contributing to dysregulated trafficking of FHH/NSHPT 
      mutants. We simultaneously monitored dynamic changes in plasma membrane levels of 
      CaSR and intracellular Ca(2+), using a chimeric CaSR construct, which allowed 
      explicit tracking of plasma membrane levels of mutant or wild-type CaSRs in the 
      presence of nonchimeric partners. Expression of mutants alone revealed severe 
      defects in plasma membrane targeting and Ca(2+) signaling, which were 
      substantially rescued by coexpression with wild-type CaSR. Biasing toward 
      heterodimerization of wild-type and FHH/NSHPT mutants revealed that intracellular 
      Ca(2+) oscillations were insufficient to rescue plasma membrane targeting. 
      Coexpression of the nonfunctional mutant E297K with the truncation CaSRDelta868 
      robustly rescued trafficking and Ca(2+) signaling, whereas coexpression of 
      distinct FHH/NSHPT mutants rescued neither trafficking nor signaling. Our study 
      suggests that rescue of FHH/NSHPT mutants requires a steady state intracellular 
      Ca(2+) response when extracellular Ca(2+) is elevated and argues that Ca(2+) 
      signaling by wild-type CaSRs rescues FHH mutant trafficking to the plasma 
      membrane.
FAU - Grant, Michael P
AU  - Grant MP
AD  - Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822-2604, 
      USA.
FAU - Stepanchick, Ann
AU  - Stepanchick A
FAU - Breitwieser, Gerda E
AU  - Breitwieser GE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121017
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
RN  - Hyperparathyroidism, Neonatal Severe Primary
RN  - Hypocalciuric hypercalcemia, familial, type 1
SB  - IM
MH  - Calcium/metabolism
MH  - Calcium Signaling/*genetics
MH  - Cell Line
MH  - Cell Membrane
MH  - Endoplasmic Reticulum/metabolism
MH  - Fluorescence Resonance Energy Transfer
MH  - Genotype
MH  - HEK293 Cells
MH  - Humans
MH  - Hypercalcemia/*congenital/genetics/metabolism
MH  - Hyperparathyroidism, Primary/*genetics/metabolism
MH  - Infant, Newborn, Diseases/*genetics/metabolism
MH  - Protein Transport/*genetics
MH  - Receptors, Calcium-Sensing/*genetics/metabolism
PMC - PMC5416950
EDAT- 2012/10/19 06:00
MHDA- 2013/06/21 06:00
PMCR- 2013/12/01
CRDT- 2012/10/19 06:00
PHST- 2012/10/19 06:00 [entrez]
PHST- 2012/10/19 06:00 [pubmed]
PHST- 2013/06/21 06:00 [medline]
PHST- 2013/12/01 00:00 [pmc-release]
AID - me.2012-1232 [pii]
AID - 3808303 [pii]
AID - 10.1210/me.2012-1232 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2012 Dec;26(12):2081-91. doi: 10.1210/me.2012-1232. Epub 2012 Oct 
      17.