Smooth muscle and hormones Flashcards
How does actin and myosin affect muscle contraction- smooth muscle
- Action potential arrives at the smooth muscle cells causing sodium channels to open and sodium influx, this will cause depolarisation.
- Depolarisation open the voltage gated calcium ion channels causing calcium ion influx from the extracellular space
- Calcium ions bind to calmodulin to form a calcium-calmodulin complex.
- The calcium-calmodulin complex activates the myosin light chain kinase (MLCK).
- MLCK phosphorylates the myosin heads.
- The phosphorylated myosin heads form cross bridges with the actin filament.
- The sliding filament power stroke occurs
- Myosin light chain phosphatase (MLCP) dephosphorylate the myosin head, stopping the cross-bridge.
- Ca+2 pumps return intracellular Ca+2 to normal.
Difference in smooth muscle compared to skeletal muscle
Ca+2 influx, cross bridge formation (activity of MLCK) and Ca+2 removal takes longer in smooth muscle compared to skeletal muscle. Smooth muscle is more stretchable allowing organs to expand whilst retaining their ability to contract.
Where is smooth muscle found
GI tract, airways, skin and blood vessels
Structure of smooth muscle cell
Smooth muscle is spindle shaped, it is thickest in the middle whilst it tapers at each end, it also has a centrally located nucleus. It has dense bodies which anchor the thin filament. It contains thick and think filament for contraction of the muscle cell. The sarcoplasmic reticulum is located very close to the caveolae, which are indentations of the plasma membrane. The caveolae increases the surface area of the plasma membrane and has a high density of voltage gated calcium channels. Can be organised in single or multi-units
Single unit smooth muscle cells
The cells work as one body, when one cell depolarises the others do as well. The cells are connected by gap junctions so ions flow freely between the smooth muscle cells
Multi unit smooth muscle cells
The cells are separated from each other so when one cell depolarises it does not mean that the others will depolarise.
Skeletal muscle structure
1) Composed of multiple muscle fascicles which are wrapped together in the epimysium.
2) Each fascicle is composed of bundles of muscle fibre that are wrapped in the perimysium.
3) The perimysium separates the fascicles from each other.
4) Each muscle fibre is an individual muscle cell wrapped in endomysium.
5) It contains myofibrils which are made of thick (myosin) and thin (actin) filaments.
Structures within the myofibril
Sarcolemma- plasma membrane
Sarcomere- repeated contractile units between two Z-disks
Transverse (T) tubule- extension of the sarcolemma which penetrates deep into the muscle fibre, connected to sarcoplasmic reticulum
Sarcoplasmic reticulum- specialised ER which stores calcium ions
Triad- combination of sarcoplasmic reticulum and T-tubule which interact via the terminal cristernae
Structure of sarcomere
M line- centre of sarcomere
I band- area which contains only thin (actin) filament
Z band- centre of thin actin filament, between two Z bands is a sarcomere
A band- Where there is thick (myosin) filament, the darker region is where there is overlap between the the thick and thin filament. The lighter region is where there is only the thick filament and is the H zone.
Troponin-tropomyosin complex
Interacts with the actin filament. made of 3 types of Troponin. One is Troponin T which binds to tropomyosin, then Troponin C which binds calcium ions and finally Troponin 1 which binds actin. The myosin binding site is blocked by the troponin-tropomyosin complex.
Contraction of skeletal muscles (excitation-contraction model)
1) When an action potential arrives at the terminal axon in the neuron it triggers calcium influx and fusion of the synaptic vesicles with the presynaptic membrane, at the neuromuscular junction.
2) The ACh will diffuse across the synaptic cleft and will bind to the N1 receptor. These are coupled with the sodium ion channels which will open allowing sodium influx and depolarising the sarcolemma and the T-tubule.
3) This depolarisation will cause the opening of the calcium ion channels in the sarcoplasmic reticulum, calcium enters the cytoplasm.
4) The Calcium binds with tropanin C, inducing a confirmation change in the troponin-tropomyosin complex.
5) The complex removes itself exposing the myosin binding site, allowing the actin to interact with myosin. Causing cross bridges to form and muscle contraction.
Relaxation of skeletal muscle
The calcium ions will be pumped back into the sarcoplasmic reticulum. Terminating the contraction event. As there is no calcium available, the troponin-tropomyosin complex will block the myosin binding site on the actin, meaning no cross bridge can form.
The sliding filament theory of muscle contraction
- The ATP on the myosin head is hydrolysed to ADP and inorganic phosphate. The myosin head undergoes a conformation change, getting it ready to attach to the actin.
- Myosin head attaches itself to the myosin binding site on the actin, forming a cross-bridge.
- The myosin filament pulls the actin filament towards the M-line, this is a power stroke and causes the myosin head to become smaller.
- The ADP and inorganic phosphate are released from the myosin head and a new ATP molecule is attached to the myosin head.
- This attachment with ATP detaches the myosin head from the actin, allowing more cross-bridges to be formed.
- The ATP hydrolyses causes a change in the conformation of the myosin head and the process is repeated.
Hormone
A chemical messenger synthesised by a specific tissue and secreted into the blood stream where it is carried to a non-adjacent site in the body to exert its action. They are secreted by glands in the endocrine system and control and regulate processes like homeostasis and reproduction
The endocrine system
Means internal secretion, tissues which release hormones are known as endocrine tissues
Endocrine signalling
A cell signals to a distant cell via a chemical messenger released in the circulatory system
Paracrine signalling
A cell communicates to a cell next to it, i.e. a neighbouring cell in the same tissue
Autocrine signalling
A cell signals to itself i.e. the same cell that released the chemical is stimulated. Cytokines often use this type of signalling.
Synaptic or Neurocrine signalling
A neuron signals to a cell using neurotransmitters. This signalling is really just a special type of paracrine signalling.
Hormone control- negative feedback
When the hormone is no longer needed and homeostasis is achieved the pathway is shut off. As rising levels of the hormone are detected a signal will be sent to reduce its release. Prevents the system from becoming overactive as the mechanism is inhibited by its own products. It decreases the response and brings it back to the set (homeostatic) point. Example- insulin and ADH
Hormone control- neuronal, substrate and tropic
Neuronal stimulation is when hormones are released due to the action of neurons i.e CRH. Tropic hormones are released in response from another hormone, i.e. ACTH. Substrate control is when the hormone is directly influenced by the circulating volumes of the substrate it is controlling, like glucose and insulin.
Hormonal control- positive feedback
Amplifies a particular response so that it deviated further from the set (homeostatic) point. Requires an external factor to break the positive feedback loop. Example- oxytocin during childbirth
Hypothalamic-pituitary axis
The Hypothalamus is located at the base of the forebrain. It can receive circulatory inputs (from the blood stream) and neuronal inputs (emotions). The inferior part of the hypothalamus gives rise to the pituitary stalk. The pituitary gland is split into two lobes, the anterior pituitary and the posterior pituitary. Provides a link between endocrine and neuronal system
The two lobes of the pituitary gland
The posterior pituitary gland (Neurohypophysis) stores hormones made by the hypothalamus, and the anterior pituitary gland (adenohypophysis) synthesises hormones. In both lobes the hypothalamus controls the secretion of hormones by the pituitary, the mechanisms are very different.
How the posterior pituitary gland is control
Neurohormones from the hypothalamus are secreted directly into the capillary plexus which is in the posterior pituitary so they can be stored
How the anterior pituitary gland is controlled
stimulatory and inhibitory neurohormones from the hypothalamus are secreted into the extracellular fluid at the median eminence. They can then be picked up by the capillary plexus and transported down the portal vein into the secondary capillary plexus where they can be released into the anterior pituitary gland. Effecting whether it produces hormones. Each hormone is synthesised by a particular troph which is a collection of cells named after what they produce.
Growth hormone (GH)
Synthesised by= Somatotrophs in the anterior pituitary gland Stimulated by= GHRH Inhibited by= GHIH & IGF-1 Target organ= Liver Effect= stimulates growth
Thyroid stimulating hormone (TSH)
Synthesised by= Thyrotrophs in the anterior pituitary gland
Stimulated by= TRH
Inhibited by= T3
Target organ=Thyroid organ
Effect= stimulates throid hormone release
Follicle stimulating hormone (FSH) and Luteinizing hormone (LH)
Synthesised by= Gonadotrophs in the anterior pituitary gland
Stimulated by= GnRH & sex steroids
Inhibited by= prolactin and sex steroids
Target organ= reproductive organs
Effect= Stimulates sex steroid production
Prolactin
Synthesised by= Lactotrophs in the anterior pituitary gland
Stimulated by= PRF & TRH
Inhibited by= Dopamine
Target organ= Mammary glands and reproductive organs
Effect= Stimulates milk production
Adrenocorticotropic hormone (ACTH)
Synthesised by= Corticotropes in the anterior pituitary gland Stimulated by= CRH Inhibited by= Glucocorticoids Target organ= Adrenal cortex Effect= stimulates cortisol release
Hormones produced by the posterior pituitary gland
Oxytocin- causes contraction on smooth muscle in the uterus leading to birth and in the mammary gland leading to milk ejection. Antidiuretic hormone (ADH)- increases permeability of collecting duct
Diseases caused by dysregulation of hormone production in the HP axis.
Acromegaly: Excess growth hormone production by pituitary gland after the growth plates are formed, leaving to enlarged organs and physical deformities
Cranial diabetes insipidus: ADH deficiency due to lack of hypothalamic synthesis, leads to increases thirst and dilute urine
Synthesis of steroid hormones
CHOLESTEROL is converted to PREGNENOLONE by the enzyme desmolase, it removes 6 carbons from ring D in the mitochondria. Pregnenolone is then converted to progesterone by enzymes in the mitochondria and cytoplasm. This involves isomerisation, the double bond moves from ring B to ring A. The hydroxyl group on ring A becomes a keto group. Steps after this are variable but progesterone tends to be converted into androgens (testosterone) or mineralocorticoids (aldosterone)
Steroid hormone release
Released immediately by diffusing out of the cell. Rate of release depends on rate of synthesis. They are lipid soluble so travel in the blood attached to plasma proteins
How steroid hormones act on receptors
The hormones diffuse across the plasma membrane and bind to intracellular receptors on the hormone binding site, they can be on any organelle in the cytoplasm. This will cause a shape change due to the flexible hinge region. The inhibitory protein will move away from the receptor exposing the DNA binding site. The activated hormone will travel to the nucleus (if it isn’t already there) and bind to the hormone response element of DNA which will affect transcription of specific genes. Increasing or decreasing the synthesis of mRNA. The mRNA will then be translated to a protein altering cell activity.
Cell surface receptors
Used for polypeptide and modified amino acids hormones as they cannot cross the cell membrane, The hormone binds to the extracellular domain causing a conformational change in the intracellular domain allowing it to pass on the message via transduction via relay proteins and second messengers. This activates our cellular processes.
G-protein coupled receptor
G protein has three subunits; alpha, beta and gamma. In the resting state the alpha sub-unit has GDP bound to it, with the beta and gamma bound to the alpha subunit. When the hormone binds to the extracellular surface of the receptor, the G protein complex changes shape, losing GDP and gaining GTP, this cause the alpha subunit to split away from the beta and gamma subunit. The alpha subunit is activated which will phosphorylate and activate an effector protein using the phosphate from GTP as its hydrolysed to GDP. The effector protein will activate a second messenger such as cAMP, which could trigger an enzyme cascade bringing about a change in cellular response.
Tyrosine kinase receptor
The Tyrosine kinase receptor contains the alpha and beta subunit which are two monomers. When a hormone binds to a receptor it causes a change in shape, which will causer dimerization, so the two monomers will become physically closer together. This will activate the kinase and cause phosphorylation of our intracellular tyrosine residues using energy from ATP. As the ATP breaks down into ADP and phosphate which will phosphorylate the tyrosine. The phosphorylated tyrosine residues can now bind to specific relay proteins which can trigger an enzyme cascade and cause different cellular responses often via signal transduction pathways. Used by insulin
Intracellular receptors
are used for steroids and hydrophobic hormones. In its resting state the intracellular receptor is in the cytoplasm. When the hormone crosses the plasma membrane it binds to the intracellular receptor causing a conformational change, activating the receptor. The hormone and receptor together will enter the nucleus (unless they are already there) and bind to specific sections of the DNA called hormone response elements. This will cause a change in protein synthesis by either inhibiting or stimulating the transcription of certain genes.
Adenylate cyclase
An effector protein which converts ATP to cAMP, which is a second messenger. It can trigger protein kinase and trigger a range of cellular responses such as opening an ion channel. This is used by glucagon, FSH, ACTH and others.
Phospholipase C
Acts as an effector protein. Acts on PIP2 which is in the membrane. PIP2 breaks down into IP3 and DAG. IP3 binds to the endoplasmic reticulum, opening a ligand gated ion channel releasing calcium into the cytoplasm which can activate multiple cellular responses. IP3 is the second messenger. Used by catecholamines, ADH, oxytocin and others.
Steroid hormones
Synthesised from cholesterol. . Because they are soluble in fat they can pass through the plasma membrane and bind to intracellular receptors. Because they are hydrophobic they can not travel freely in the bloodstream but bind to plasma proteins. They act on the nucleus meaning they have a slow mechanism of action. Example= cortisol
Non-steroid hormones
Divided into polypeptide hormones and modified amino acid hormones. Polypeptide hormones are the majority of hormones ie insulin. Modified amino acid hormones are made from tyrosine and trytophan precursors ie adrenaline. Non-steroid hormones are water soluble but not fat soluble meaning they have to bind to receptors on the cell surface membrane and cant pass straight through. So they exert their effects on the membrane not the nucleus, so are fast acting
Polypeptide hormone synthesis, storage and release
Synthesised through transcription and translation. Stored in secretory vesicles as the hormone is water soluble and can not just diffuse out of the cell. The vesicles are released by exocytosis, they fuse with the plasma membrane then release their contents outside the cell.
Amino acid hormone synthesis, storage and release
Synthesised from a precursor, either Tyrosine or Tryptophan. Stored in secretory vesicles and released by exocytosis, diffuse in the blood. The thyroid hormone works differently.
Adrenal gland
Controlled by the Hypothalamus-pituitary-adrenal-axis. Part of the sympathetic nervous system. It is located above the kidneys and is divided into two layers- adrenal medulla and adrenal cortex, there is a capsule around the outside of the two layers.
Hypothalamus-pituitary-adrenal-axis
The Hypothalamus detects the stress and releases CRH. This acts on the anterior pituitary gland causing the release of ACTH. This acts on the endocrine tissue of the adrenal gland which will release cortisol. Direct stimulation from the sympathetic nervous system causes adrenaline to be release.
Adrenal medulla
- Controlled by sympathetic nervous system
- Made of types of neuro-endocrine cells. The neuro-adrenaline secreting cells and the adrenaline secreting cells.
- Secretes catecholamines (modified amino acid hormones). They are stored in neuro-endocrine granules and are released in response to a fight or flight response. Increases heart rate
Adrenal cortex
Primarily regulated by ACTH. Divided into the zona glomerulosa, zona fasciculata, and zona reticularis. All secrete steroid hormones
Zona glomerulosa
Secretes mineralocorticoids (aldosterone) to regulates sodium reabsorption and blood volume, very small. Outside layer next to capsule
Zona faciculata
Composed of rod like cells which secretes glucocorticoids (mainly cortisol) - involved stress response, increasing blood glucose levels. Bigger. Middle layer
Zona reticularis
Secretes the androgen precursor, DHEA (dehydroepiandosterone) & glucocorticoids. Innermost layer nest to the medullary vein
Dysregulation of the adrenaline gland
- Endocrine function of the adrenal gland must be tightly regulated
- Excess aldosterone - water retention leading to hypertension. Can be caused by tumour (Conn’s syndrome) or excess medication and other disorders
- Excess cortisol - Cushing’s syndrome. Can lead to fat deposits and personality changes. Can be caused by tumour (Cushing’s disease) or excess medication
- Adrenal cortex insufficiency (less cortisol and aldosterone) - Addison’s disease (destruction of cortex) or caused by secondary disorders of hypothalamus and pituitary gland.
