내몸 ≫ 감각기관 ≫ 수용체

칼슘신호 Calcium signaling

신경전달물질 : 2차 전령
- NO, CO
- cAMP,  칼슘, 칼슘 영상기법

칼슘 역할
- 칼슘과 응고
- 칼슘의 독성

칼슘이온 (Ca2+)
칼슘 이온은 IP3 와 DAG 기능은 물론 세포내의 중요한 이차 전령물질이다. 정상적으로 세포 내 칼슘 레벨은 매우 낮지만 다음의 경우에는 세포 내 칼슘 농도가 극적으로 증가한다. 그러나 세포막의 voltage-gated channel이 세포 외 액으로부터 세포 내로 끌어들일 때와 ER및 미토콘드리아 같은 세포 내 저장고에서 세포질로 방출될 때.
세포 내 칼슘 이온의 증가는
1) 근육 수축
2) 신경 접합 부위에서 신경 전달 물질의 방출
3) PKC에 의해 중개된 생화학적 변화-세포 내 표적 단백질의 인산화시키는 칼슘 의존적 효소

 

 

 



 

Some Proteins Regulated by Ca2+ and Calmodulin
- Adenylyl cyclase (brain)
- Ca/calmodulin-dependent protein kinases (CaM kinases I to IV)
- Ca-dependent Na channel (Paramecium)
- Ca-release channel of sarcoplasmic reticulum
- Calcineurin (phosphoprotein phosphatase 2B)
- cAMP phosphodiesterase
- cAMP-gated olfactory channel
- cGMP-gated Na
, Ca channels (rod and cone cells)
- Glutamate decarboxylase
- Myosin light chain kinases
- NAD kinase
- Nitric oxide synthase
- Phosphoinositide 3-kinase
- Plasma membrane Ca ATPase (Ca pump)
- RNA helicase
- 배 발생의 개시
- 골격근, 심근, 평활근 등의 수축
- 신경세포 축색 중의 물질의 수송
- 원형질 유동, exocytosis, endocytosis
- 세포의 변형운동
- Microvilli의 운동
- 세포분열
- 세포막 유동성
- 특이적인 Ca2+ 결합단백질을 매개로

 

Despite tremendous diversities in their expression, cellular activities in virtually all cell types are regulated by common intracellular signaling systems, and calcium is one important ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation (Ref.1). In response to adequate stimuli, [Ca2+]i (Intracellular Ca2+ concentration) increases, oscillates and decreases, leading to the activation, modulation and termination of cell function. Numerous channels and pumps allow this particular cation to enter and exit cells and move between the cytosol and intracellular stores.

The Ca2+ signaling apparatus includes 1) the RyR (Ryanodine Receptor Channels) that is the SR (Sarcoplasmic Reticulum) Ca2+ release channel, 2) the Troponin protein complex that mediates the Ca2+ effect to the myofibrillar structures leading to contraction, 3) the Ca2+ pump responsible for Ca2+ reuptake into the SR, and 4) Calsequestrin, the Ca2+ storage protein in the SR. In addition, a multitude of Ca2+-binding proteins is present in muscle tissue including annexins, sorcin, myosin light chains, β-Actinin, Caln (Calcineurin), and Calpain (Ref.2). When calcium signaling is stimulated in a cell, Ca2+ enters the cytoplasm from one of two general sources: it is released from intracellular stores, or it enters the cell across the plasma membrane. The mechanism of regulated Ca2+ entry in non-excitable cells is through a process known as capacitative Ca2+ entry or store-operated Ca2+ entry, in which the depletion of intracellular stores due to the action of IP3 (Inositol Trisphosphate) or other Ca2+-releasing signals activates a signaling pathway leading to the opening of plasma membrane Ca2+ channels (Ref.3). In excitable cells, the major pathway for Ca2+ influx is via highly Ca2+-selective VGCC (Voltage-Gated Ca2+ Channels). In skeletal muscle cells, an additional voltage-sensitive pathway is provided by DHPR (Dihydropyridine Receptors) that is physically coupled to RyR on the Sarco- and ER (Endoplasmic Reticulum) membrane. Many Ligand-Gated Ionotropic Channels NMDA (N-methyl-D-aspartate), AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Proprionate), Kainate, AchR (Nicotinic Acetylcholine Receptor), Serotonin (5HT3), and ATP (P2X) admit significant amounts of Ca2+ through its receptors. Store Operated Channels open in response to emptying of intracellular stores through the interaction with IP3 and its receptor (IP3R). CRAC (Ca2+-Release-Activated Ca2+ channel) is found in cells of the blood lineage and is highly Ca2+-selective. TRP (Transient Receptor Potential) are nonspecific cation channels, which is subdivided into three groups TRPC, TRPV and TRPM. TRPC channels respond indirectly to Hormones and Transmitters through PLC-β (Phospholipase-C) activation and via second messengers such as DAG (Diacylglycerol), Spinghosine, ADP-Ribose, Arachidonic Acid and other unidentified signals. TRPV and TRPM families are directly or indirectly responsive to numerous sensory stimuli such as temperature and Osmolarity (Ref.4 & 6).

Other voltage-independent channels respond to sensory stimuli. Hair cells of the ear have mechanically opened Ca2+-permeant channels. Light, Odorants and Taste molecules operate through a signal cascade that includes activation of AC (Adenyl Cyclase) and GC (Guanylate Cyclase), and subsequent opening or closing of CNG (Cyclic Nucleotide Gated) Channels whose gating is regulated by the cyclic nucleotides cAMP (cyclic Adenosine 3', 5’-Monophosphate) or cGMP (cyclic Guanosine Monophosphate) through G-proteins; GN-αS, GN-αT and GN-α-Olf. Voltage-independent pathways are generally activated by signaling cascades and the most common pathway involves activation of PLC and generation of IP3 and DAG from PIP2 (Phosphatidylinositol (4, 5)-Bisphosphate). Hormones and Neurotransmitters bind to GPCR (G-Protein Coupled Receptors). Both the heterotrimeric GN-αQ/GN-α11 and GN-αI/GN-αO proteins regulate the function of PLC-β. GPCR coupling to GN-αI/GN-αO activate PLC-β, through the GN-β and GN-γ subunits that are liberated in large quantities (Ref.7). Other members of the PLC family are activated by Growth Factors that activate RTK (Receptor Tyrosine Kinases; PLC-γ), Ras (PLC-Epsilon), and intracellular Ca2+ (PLC-Delta). PLC-γ is also activated by Antigen-stimulated activation of non-RTKs such as Src via binding to TCRs (T-Cell Receptors) and BCRs (B-Cell Receptors) (Ref.6). Ca2+ release from the intracellular stores is mediated by RyR and IP3R channels. RyR are activated by a rise in intracellular CICR (Ca2+-Ca2+ Induced Ca2+ Release). In addition there are RyR-like channels activated by cADPR (cyclic ADP-ribose) (Ref.5), Sphingosine and a distinct Ca2+-release pathway activated by NAADP (Nicotinic Acid Adenine Dinucleotide Phosphate). Within Ca2+-storing organelles, Ca2+ ions are bound to specialized Ca2+-buffering proteins like CS (Calsequestrins), CR (Calreticulins) and CN (Calnexins). In the cytosol, there are mobile Ca2+ buffers; the CB (Calbindins), PV (Paravalbumin), Calm (Calmodulin) and S100 protein families that blunt Ca2+ spikes and assist in redistribution of Ca2+ ions (Ref.6).

In contrast to the striking variety of mechanisms for inducing extracellular Ca2+ influx, Ca2+ extrusion to the extracellular space is largely limited to two families of proteins: the PMCA (Plasma Membrane Ca2+ ATPase) and the NCX (Na+/Ca2+ Exchanger). Intracellular Ca2+ is also lowered by Ca2+ uptake into cellular organelles via a variety of organelle-specific pumps and transporters. Uptake into the ER is regulated by the SERCA (Sarco- and Endoplasmic Reticulum Ca2+ ATPase) family. Uptake into mitochondria is mediated by the mitochondrial Ca2+-Uniporter and uptake into Golgi is mediated by the PMR1/ATP2C1 (P-type Ca2+-transport ATPase). Mitochondria release Ca2+ via the mitochondrial NHE (Na+-H+/Ca2+ Exchanger) and, under some circumstances, the PTP (Permeability Transition Pore) (Ref.6). Cytoplasmic Ca2+ signals propagate to the nucleus, where they directly stimulate the synthesis of immediate early genes as well as structural genes. Activation of Ca2+-dependent transcription requires both cytoplasmic and nuclear Ca2+ signals. Ca2+ influx through synaptic NMDA Receptors activates CREB (c-AMP Response Element-Binding Protein), whereas influx through extrasynaptic NMDA Receptors inhibits CREB. Ligand-Gated Channels use the cytoplasmic Ca2+ sensor, Calm (Calmodulin), to sense local Ca2+ elevations and activate a PKA-dependent Rap1-MAPK/ERK (Mitogen-Activated Protein Kinase/ Extracellular Signal-Regulated Kinase) Pathway (Ref.8). CalmKII and CalmKIV (Calm Kinase-II and IV) phosphorylation of CBP (CREB Binding Protein) and Histone Deacetylases, HDAC4, HDAC5 and HDAC7 mediate some nuclear Ca2+ signals. HDAC export allows MEF2 (Myocyte Enhancing Factor-2) to activate transcription by recruiting other Ca2+-sensitive transcriptional factors such as NFAT (Nuclear Factor of Activated T-Cells) and transcriptional coactivators such as p300 in the CRE (cAMP Responsive Element) region. Nuclear Ca2+ also activates Caln, which dephosphorylates NFAT and promotes its transcriptional activity (Ref.9).

Ca2+ is an important early messenger that is important for wound repair and for the initiation of cellular events such as the fertilization of oocytes, muscle contraction and hormone and peptide secretion (Ref.10). Buffering of intracellular Ca2+ transients in human neutrophils leads to reduced motility due to defective uropod detachment on fibronectin and vitronectin-coated surfaces. Recently, subtler forms functional alterations of several Ca2+ signaling and handling molecules have been found to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, certain forms of myopathies (related to channel malfunctioning), and malignant hyperthermia (related to Ca2+-releasing RyR mechanisms) (Ref.2). The degeneration of the retina is caused by gene defects of neuronal calcium sensors. Calpain has also been involved in a number of diseases like the limb girdle muscular dystrophy Type 2A (Calpain-III), and the Type 2 Diabetes (Ref.11).

애기장대(Arabidopsis thaliana) 꽃의 합성에 칼슘전류가 신호.

여섯 개의 웅성생식기관(꽃밥)에는 꽃가루 알갱이(내부의 파란색 점)가 들어있고, 중앙의 자성생식기관(씨방)에는 두 줄의 밑씨(하늘색)가 들어있다. 암술머리는 암술의 꼭대기에서 꽃가루를 받는 곳으로, 수많은 돌기가 솟아있어 꽃가루가 많이 부착될 수 있다. 암술머리 위에 붙은 꽃가루가 형성한 꽃가루관(오렌지색 선)이 암술대를 통과하여 밑씨를 향해 내려가고 있다.
성장하는 꽃가루관을 특징짓는 것은 칼슘전류이며, 칼슘전류는 꽃가루관 말단의 성장과 밀접한 관계가 있다. Wudick et al.은 이번 주 《Science》에서, 글루타민 수용체 유사채널(GLRs: glutamate receptor–like channels)을 분류하고 운반하는 단백질군(群)인 CORNICHON의 작용을 상세히 기술했다(http://science.sciencemag.org/content/360/6388/533).
세포 내부에서 GLRs의 위치는 CORNICHON에 대한 복잡한 반응을 통해 결정된다. CORNICHON은 일부 GLRs를 원형질막으로, 다른 GLRs는 칼슘저장소로 운반한다. 따라서 성장하는 꽃가루관 말단의 칼슘전류는 세포내의 여러 가지 전류를 통합한 결과물이라고 할 수 있다. CORNICHON은 이런 식으로 칼슘전류를 통제하여 꽃가루관의 성장과 씨앗의 생성에 영향을 미친다.

천식에 칼슘감지 수용체가 작용

최근 영국 카디프대 연구진이 천식의 잠재적인 근본 원인을 밝히고 기존 약제를 이용한 새로운 치료 구상을 내놨다. 이들 연구팀은 영국 킹스컬리지, 미국 메이요 클리닉 과학자들과의 공동연구를 통해 전에는 역할이 규명되지 않았던 ‘칼슘 감지 수용체’(CaSR)가 바로 천식을 일으키는 원인이라고 ‘과학 중개 의학(Science Translational Medicine)’ 최근호에서 소개했다.
연구팀은 특히 칼실리틱스(calcilytics)로 알려진 제약군이 효과가 높다는 점을 강조해 눈길을 끌었다. 이 약들은 환자의 환경과 연계된 모든 증상, 즉 기도 협착과 수축, 기도염과 같이 숨쉬기를 어렵게 하는 모든 증상을 반전시키도록 CaSR을 조절하는 역할을 하는 것으로 조사됐다.
주 연구자인 다니엘라 리카디(Daniela Riccardi) 카디프대 생명과학부 교수는 “믿기 힘들 만큼 놀라운 연구 결과가 나왔다”며, “우리는 처음으로 알레르겐이나 담배연기, 차량 매연과 같은 환경적 촉발요인에 의한 기도 염증과, 알레르기성 천식으로 인한 기도 수축 사이의 연관관계를 찾아냈다”고 밝혔다.
칼실리틱스는 약 15년 전 골다공증 치료를 위해 처음 개발됐다. 당시는 CaSR이 아나볼릭 호르몬 분비를 유도토록 해 약화된 뼈를 강화하려는 목적이었다. 그러나 안전하고 인체 적응성이 높았으나 골다공증 치료에는 성공적이지 못 했다. 그러다 최근 들어 천식연구자들의 눈에 띄어 천식 치료제 후보로 재등장하게 됐다. 연구팀은 기금을 확보하는 대로 2년 안에 사람을 대상으로 임상시험을 실시할 계획이다.
리카디 교수는 “칼실리틱스를 사람의 폐에 직접 투여해도 안전하다는 것이 증명되면 5년 안에 이 방법으로 환자들을 진료하게 돼 천식을 바로 첫 단계에서 치료할 수 있을 것”이라고 말했다.


 

 

 

 

 


 

흥분독소, 세포사멸의 진범은 칼슘이다