Mapa mental

Calcium homeostasis

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Mind map: Calcium homeostasis

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Calcium homeostasis

Hypocalcemia
- in low Ca, NS becomes progressively more excitable
  - due to increased permeability of neuronal membranes to Na ions
- hyperactivity causes tetanic muscle contractions and cramps
- causes pore mineralisation of bones
  - osteoporosis- weak bones
- impaired growth and rickets in children
- Moans, Stones, Groans and Bones
  - Moans - gastrointestinal problems
  - stones- kidney conditions
  - groans- physiological conditions
  - Bones- pain and related conditions
Roles of Calcium
- bone and teeth rigidity
- muscle contraction
- membrane stability
- neurotransmitter release
- secretory processes
- DNA/RNA synthesis
- blood clotting
  - if calcium is to low you would bleed to death
- calmodulin - enzyme regulation
Regulation of calcium balance
- parathyroid hormone (PTH)
  - increases fractional reabsorption into the kidney
- 1,25-dihydroxy vitamin D
  - calcitrol stimulates reabsorption to the plasma
- Calcitonin
  - inhibits reuptake from he bone
- regulation of Ca absorption, reabsorption, and excretion
  - from bone, kidney and intestine
Parathyroid hormone
- synthesised in chief cells of parathyroid gland
- stored as pre-pro or pro-hormone
  - biological active 84AA peptide
- targets bone and kidney
- hypercalcemic action on the body
  - elevates blood calcium
- thyroidectomy - removal of parathyroid gland
  - fatal if not for small clusters of PTH secreting cells outside PT gland
- secretion is controlled via CaSR
  - Ca sensing receptor - on surface of PTH cells
    - High [Ca]ecf- inhibition of PTH release
    - Low [Ca]ecf - no inhibition of PH release
  - CaSR activates PLC
    - inhibits Adenylate Cyclase
      - increase intracellulae Ca via generation of IP3
        decrease in cAMP
        prevents exocytosis of PTH - INHIBITION
- HYPERPARATHYROIDISM
  - loss of Ca homeostasis due to excessive PTH secretion
  - combined effects of PTH-induced bone reabsorption, intestinal Ca absorption and renal tublule absorption
- HYPOTHYROIDISM
  - inadequate Vit D response to hypocalcemia
  - often multifactoral
  - associated with hypoparathyroidism
  - bihormonal - decrease in Vit D
Calcitonin (CT)
- 32 AA polypeptide
- released from parafollicular cells of parathyroid gland
- hypocalcaemic in action
  - reduces blood calcium levels
- ANTAGONISES PTH
  - released in response to circulating Ca
- the bone - decreased activity of osteoclasts and osteoblasts
  - crucial in controlling amount of bone tissue
    - osteoblasts- form bone tissue
    - oseteoclasts - reabsorb bone tissue
- increases production of inactive Vit D
- has little function in adults - deficiencies has little effect
- simple feedback mechanism
  - If Ca increases so does CT
  - as Ca falls the thyroid produces less CT
- target cell = Osteoclasts
- CT acts on GPCR to increase cAMP
  - inhibits osteoclast motility - alters shape and inactivates
- administration causes rapid fall in Ca caused by inhibition of bone reabsorption
  - more depositation of Ca into bone - less circulating
balancing act between PTH and CT
- Calcitonin
  - if Ca too high
  - increases Ca deposition in bones
  - decreases Ca uptake by the intestines
  - decreases Ca uptake from the urine
  - DECREASES BLOOD Ca
- Parathyroid hormone
  - if Ca is too low
  - increases Ca release from the bone (reabsorption)
  - increases Ca uptake from the urine
  - creases Ca uptake by the intestines
  - INCREASES BLOOD Ca
Vitamin D / calcitrol
- aquired from 2 sources
  - skin - via UV radiation
  - ingested in the diet
- vitamin D itself is inactive
  - requires modification to active metabolite - Vit D 3
  - not classic hormone
- active Vit D is considered a hormone as it acts upon distant target cells to evoke responses
- active Vitamin D3 is produced via removal of methylated residue. Calcitrol is then produced by two further hydroxylations in the liver and kidney.
- increases GI calcium and phosphate absorption and renal calcium absorption
- calcitrol
  - increases the activity of both osteoclasts and osteoblasts to increase the rate of bone remodelling
- active Vit D is a major regulator of Ca
- increases Ca absorption from the intestine and reabsorption from bone
  - increases blood calcium
- active Vit D is lipid soluble
- binds to typical nuclear receptor(VDR) - analogus to steroid hormones
- travels in the blood bound to hydroxylated a- globulin
- action on bones
  - promotes resorption
  - osteoblasts (not osteoclasts) have Vit D receptors
  - Vit D3 acts on osteoblasts
    - paracrine signalling
      - activates osteoclasts
        Ca resorption from bone matrix
  - inadequate supply of Vit D= rickets
intracellular Ca homeostasis
- precisely regulated
- calcium can be stored in mitochondria, ER and be free/ bound in the cytoplasm
- influx mechanisms
  - entry via ligand gated ion channels
  - Ca leak via passive bilayer diffusion
  - entry via gap junctions
- patch clamp analysis - aids understanding of Ca channels
- Calcium channels
  - L-type - strong depol, current activates ca currents of long duration
    - inhibited by Nifedipine
  - T-type - Weak depol, current activates rapidly. Inactivated voltage dependent manner
    - insensitive to l-type inhibitors
  - N-type - Require strong Depol, current for activation, Inactivation moderately rapid.
    - Insensitive to DHP inhibitors but not conotoxin
  - P-type- Medium depol, current activates
    - sensitive to funnel web spider toxin
  - ORAI- STIM channels
    - calcium release-activated calcium channel
    - activated upon the depletion of internal calcium stores
    - upon activation by PLC they form IP3 to activate channels releasing calcium from internal ER stores
    - depletion of internal Ca stores is detected by STIM proteins - STIM translocates to nearer the PM and interacts with ORAI proteins - to open Ca channels = influx into the cell - more Ca uptake by the ER to replenish stores
- receptor activated Ca-influx
  - not voltage dependent (on membrane)
  - activated in response to intracellular messengers
  - activated in response to interaction with GPCR
  - binding of an agonist conducts Ca like the Ach R - Ach binding = Na flow
- Ca efflux
  - ATP driven Ca-ATPase
    - ~140 kDa PM bound protein
    - 2H for 2Ca
    - extrudes Ca against a gradient - requires energy input
    - calmodulin enhances affinity and rate of Ca efflux
    - maintains basal intracellular Ca
  - Na/Ca exchange
    - facilitates rapid efflux of Ca
    - charge imbalance - electrogenic
    - can be influenced by MP
    - energy provided by Na gradient
Ca binding and modulated proteins
- Ca Binding proteins
  - Ca buffering
  - calmodulin
  - Calretinin
  - Paralbumin
  - calmodulin has 4 HLH regions - can bind 4 Ca
- Ca Modulated proteins
  - directly effected by changes in cytosolic Ca
- HLH and non HLH structures
  - HLH = Calmodulin / troponin C / Calpain
  - non-HLH = PKC/ annexins /Ca actiavted ion channels
  - HLH structure - 12 AA residues (pocket) flanked by helical arrangement
  - HLH site allows high affinity binding of Ca
- affected biological processes
  - Ca activation of AC
  - calmodulin activated phosphodiesterase
  - Troponin C and skeletal muscle contraction
  - PK is a Ca dependent kinase
phospholipase C (PLC)
- initiates PI hydrolysis
- 6 isoforms
- classified according to structure and regulatory domains
- large amounts of phosphatidylcholine inhibits PLC
- phosphatidylserine and DAG oppose this effect
- Gi coupled GPCR inhibit PLC activity
- Ga GPCR stimulate activity of PLC
IP3 stores of Ca
- in non contracting cells mitochondria is a major store of Ca
- ER is a low capacity but high affinity store of Ca
  - vesicular compartment that takes up Ca in an ATP dependent manner
- IP3 R is a ligand gated ion channel
- requires that binding of 4 IP3 to activate the channel opening
- 260kDa protein
- similar topology to that of SR- RyR R
- IP3 can be broken down to yeild inositol or phosphorylated to IP4
- IP4 - can be degraded to inositol or have 2nd messenger functions
DAG - Diacylglycerol
- activates PKC in presence of Ca
effector regulation
- CALCIUM
  - Calpain
  - PKC
  - PLC
  - PLA-2
  - ion channels
  - Adenylate cyclase
    - cAMP pathway
  - CALMODULIN
    - calcineurin
    - CAM Kinase II
    - cyclic nucleotide PDE
    - NO synthase
    - Adenylate Cyclase

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Descrição: Mapa Mental sobre Calcium homeostasis, criado por Bramblehill em 14-04-2015.
Criado por: Bramblehill
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Calcium homeostasis

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