BI513 - Lecture notes week 1-12 PDF

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BI513 HUMAN PHYSIOLOGY AND DISEASES 2Week 1 Lecture 1- Endocrine system 1 - Hormones and the endocrine systemWhat is a hormone- A chemical secreted into the bloodstream for transport to a distant tissue- All hormones bind to a target cell recepotor which may be membrane bound;cytosol; nucleus- Initi...

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BI513 HUMAN PHYSIOLOGY AND DISEASES 2 Week 1 Lecture 1- Endocrine system 1 - Hormones and the endocrine system What is a hormone - A chemical secreted into the bloodstream for transport to a distant tissue - All hormones bind to a target cell recepotor which may be membrane bound; cytosol; nucleus - Initiates a response in the target cell type. Some examples how hormones can alter target activity are: o Altering rate of enzyme reactions o Regulating transport across the cell membrane o Regulating gene expression - Alters cell activity at very low concentrations (nanomolar 10-9 or picomolar 10-12)

Hormone interactions - Synergistic: the combined effect of two or more hormones is greater than the -

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individual effects e.g. glucagon, cortisol and adrenaline in blood glucose regulation. Permissive: one hormone requires another in order to fully exert its effect. e.g. thyroid hormone required for maturation of the reproductive system in presence of gonadotropins/sex hormones, even though thyroid hormone cannot stimulate maturation of the reproductive system itself. Antagonistic: two or more hormones have opposing effects on a physiological response e.g. glucagon and insulin in blood glucose regulation

Classification of hormones: 1. Peptide hormones: short peptides (just a few amino acids) or larger proteins 2. Steroid hormones: cholesterol derivatives 3. Amine hormones: amino acid derivatiives

Peptide hormone regulation: 1. Messenger RNA on the ribosomes of the ER binds amino acids into a peptide chain called a preprohormone. The chain is directed into the ER lumen by a signal sequence of amino acids 2. Enzymes in the ER chop off the signal sequence, creating an inactive prohormone. 3. the prohormone passes from the ER through the golgi apparatus 4. secretory vesicles containing enzymes and prohormone bud off the golgi. The enzymes chop the prohormone into one or more active peptides plus additional peptide fragments 5. the secretory vesicle releases its contents by exocytosis into the extracellular space. 6. The hormone moves into the circulation for transport to its target Peptide hormone production: post translational process

Peptide hormone action via receptors

steroid hormone structure

steroid hormones action via receptors: 1. Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell 2. Steroid hormone receptors are in the cytoplasm or nucleus 3. The receptor-hormone complex binds to DNA and activates or represses one or more genes 4. Activated genes create new mRNA that moves back to the cytoplasm. 5. Translation produces new proteins for cell processes 6. Some steroid hormones also bind to membrane receptors that use second messenger systems to create rapid cellular responses. Amine hormone structure

Melatonin the amine hormone derived from tryptophan

Hormones mediate long-distance communication: (example shown is a peptide hormone)

Steroid hormones and some amine hormones (thyroid hormones) can enter cells without membrane receptors For most steroid & thyroid hormones, simple diffusion was the general consensus for many years. Around 2004, evidence was shown for carrier-mediated transmembrane transport of thyroid hormones, and this is now accepted for T3 and T4. Today, the mechanism is of membrane transport for steroid hormones is now a matter of some debate and an area of active research. Why might this be?

Lecture 2- Endocrine system 2 Hormone release: simple + complex endocrine reflex pathway regulation of hormone release - Reflex control pathways with feedback loops

- Many, but not all, involve the nervous system 1. Simple reflexes  one cell senses the stimulus and secretes hormone e.g. parathyroid hormone.  Multiple stimuli regulate secretion of one hormone e.g. insulin 2. Complex reflexes: multiple hormones acting in a hierarchy/ multiple integrating centres e.g. hypothalamic- pituitary hormones

Simple endocrine reflex: parathyroid hormone

Another simple endocrine reflex: multiple stimuli for release of a signal hormone:

Complex endocrine reflexes: hypothalamic-pituitary pathway - Anterior pituitary (adenohypophysis): true endocrine gland of epithelial origin - Posterior pituitary (neurohypophysis): extension of neural tissue connected to the hypothalamus by the infundibulum

Posterior pituitary

Secretes two hormones: 1) Oxytocin 2) Vasopressin (antidiuretic hormone) These are synthesised in the hypothalamus and transported to the posterior pituitary for storage and release

Hypothalamic neurohormones control hormone release from anterior pituitary TRH: thyrotropin releasing hormone CRH: corticotropin releasing hormone GHRH: grow hormone releasing hormone GHIH: growth hormone-inhibiting hormone GnRH: gonadotropin-releasing hormone PRH: prolactin-releasing hormone PIH: prolactin-inhibiting hormone

Anterior pituitary

- Secretes six hormone

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o Prolactin o Growth hormone (GH, somatotropin) o Follicle stimulating hormone (FSH) o Luteinizing hormone (LH) o Thyroid stimulating hormone (TSH, thyrotropin) o Adrenocorticotropic hormone (ACTH, corticotropin) Many control the secretions of another endocrine gland and hence are referred to as trophic hormones

Hypothalamic- anterior pituitary pathway

Hypothalamic-anterior pituitary pathway: negative feedback loops

- Hormones act as negative feedback signals

Lecture 3 ENDOCRINE SYSTEM 3 Endocrine disorders

Endocrine disorders three basic causes: - Hormone excess leading to exaggerated response o Due to hypersecretion e.g. as a consequence of endocrine gland tumours or other causes  Gigantism, acromegaly: pituitary adenoma  Graves disease: enlarged thyroid due to production of thyroidstimulating immunoglobulins - Hormone deficiency leading to reduced response o Due to hyposecretion e.g. as a consequence of atrophy of glands, genetic defects  Pituitary dwarfism: loss of growth hormone  Addison’s disease: tuberculosis or autoimmune atrophy of adrenal cortex  Hashimotos disease: autoimmune of thyroid gland tissue - Defects in hormone receptors or associated intracellular signalling pathways leading to altered responsiveness to hormone  Pseudohypoparathyroidism: mutations in G-protein coupled receptor  Hyperinsulinemia: downregulation of receptors due to sustained high insulin Growth hormone disorders GH excess: acromegaly + pituitary gigantism GH deficiency: pituitary dwarfism

Diagnosis of endocrine disorders: Ø Generally straightforward in simple endocrine reflexes involving only one gland, e.g. parathyroid Ø More difficult in complex endocrine reflexes, e.g. hypothalamic-pituitary system Ø Requires knowledge of feedback loops

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Primary disorders: problem in last endocrine tissue in a reflex pathway Secondary disorders: problem in endocrine tissues producing trophic hormones i.e. pituitary, hypothalamus

WEEK 2: Lecture 4- CENTRAL NERVOUS SYSTEM

Nervous system organisation

The central nervous system organisation: - The brain sits in the bony cranium - The spinal cord runs down the side (dorsal side) inside the vertebral column - The bones of the cranium and vertebral column together with membranes (cerebrospinal fluid) protect the nervous tissue

Protective layers of CNS - Bone of cranium (skull) and vertebral column- outermost layer of protection for brain and spinal cord, respectively - Meninges: protective membranes between the bone and nervous tissue - Dura mater (outer, next to bone) - Arachnoid membrane (middle) - Pia matar (inner, adheres to surface of brain and spinal cord)

- Subarachnoid space between arachnoid membrane and pia mater contains -

cerebrospinal fluid CSF Meninges and CSF provide physical protection, cushioning the neural tissue CSF also provides chemical protection as ionic composition carefully regulated

Fluid compartments of the CNS Internal volume of cranium ~1.4 litre = 1 litre cells + 0.4 litre fluid - Blood (100-150ml) - Cerebrospinal fluid: in ventricles and subarachnoid space

- Interstitial fluid: inside pia mater

Cerebrospinal fluid: CSF

- Cerebrospinal fluid:

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o Produced by the choroid plexus o Filtrate of blood that contains no blood cells, very little protein and different ionic composition o Absorbed back into the blood villi on arachnoid membrane Choroid plexus: o Lines the ventricles o Consists of transporting epithelia (derived from ependymal cells) and capillaries o Filters blood, removing cells, most protein and some other solutes

The blood-brain barrier protects the brain - 15% of the total blood pumped by the heart (1 litre per minute) goes to the brain

- Neurons require high levels of oxygen and glucose to make ATP for active transport of ions and transmitters but must be protected from toxins and potentially harmful substances such as hormones, neurotransmitters, ions blood-brain barrier: functional barrier between blood and brain interstitial fluid - Present in most regions od the brain - Absent in a few areas where direct contact with blood is requires e.g. hypothalamus to allow for neurosecretory hormone secretion and vomiting centre of medulla which monitors blood for toxins.

Blood- brain barrier - consists of specialized selectively permeable capillaries - capillary endothelial cells have tight junctions and use membrane transporters to move nutrients from blood to brain and waste in opposite direction - astrocyte foot processes surround the capillaries and secrete molecules that induce tight junction formation

CNS at its simplest - The large cerebrum dominates the brain, folded in order to fit inside - The cerebellum is the second largest region of the brain - Below the cerebrum is the brain stem which leads to the spinal cord

Anatomy of the CNS

Brain regions

Spinal cord

Lecture 5- PART 2ORGANISATION AND ANATOMY OF THE NERVOUS SYSTEM PNS Peripheral nervous system 1. Efferent o Somatic motor: efferent motor neurons that project to the skeletal muscle of the body wall/limbs and control posture and movement. o Autonomic: efferent neurons that innervate (supply with nerves) the smooth muscle of all the organs of the body and cardiac muscle of the heart. 2. afferent o sensory neurons that carry information to the CNS from sensory receptors in the peripheral organs autonomic nervous system

Autonomic pathway: anatomy - sympathetic neurons originate in the thoracic and lumbar regions of the spinal cord - parasympathetic neurons originate in the brain stem or the sacral region of the spinal cord. - all autonomic pathways consists of two efferent neurons in series.

Autonomic function Sympathetic and parasympathetic divisions often have opposing effects in the same tissue.

Autonomic balance - relative levels of sympathetic and parasympathetic activity depend on the situation - homeostatic control centres in the hypothalamus, pons and medulla influence the activity of autonomic neurons to control blood pressure, body temperature etc

Lecture 6- PART 3 NEURONS Typical structure of a neuron - synapse- region of contact between two neurons or a neuron and a muscle - presynaptic neuron- delivers a signal to the synapse - postsynaptic neuron- receives the signal

morphological classification of neurons functional categories:

Structural categories:

Glial cells - Outnumber neurons by 10:50:1 - Communicate with the support neurons in various ways - Essential for the normal function of the nervous system

Axon myelination in PNS - Hundreds of Schwan cells may myelinate a single long axon - An axon may be surrounded by up to 150 layers of myelin membrane - Nerve impulses are produced at Nodes of Ranvier

Axon myelination in CNS - In central neurons, each oligodendrocyte myelinates portion of several axons - Otherwise the process is similar to that in the PNS

Electron micrograph of myelinates and unmyelinated neurons - Myelin sheaths around axons give the tissue a white colour Hence - White matter = areas of CNS that contain a high number of myelinated axons - Grey matter = areas of the CNS that contain a high number of cells, dendrites and unmyelinated axons

Lecture 7- PART 4 SIGNALLING

Overview - all cells in the body maintain a potential (voltage) difference across the cell membrane. This is the cells membrane potential - neurons and muscle (excitable cells) can alter their membrane potential in response to stimulation - the membrane potential at rest (cells not actively signalling) is the resting membrane potential. - Changes in membrane potential give rise to action potentials - In a typical neuron, action potential (nerve impulses) are generated at the axon hillock and conducted down the axon to the presynaptic terminal. - When it reaches the axon terminal, the action potential electrical signals is passed to the associated neuron or muscle at the synapse. This process of synaptic transmission

Membrane potential All living cells have a membrane potential: - An electric potential difference across the cell membrane = a difference in electrical charge between the inside and outside of the cell

- The membrane potential at rest (cell nit actively signaling) is the resting potential

Generating membrane potential: ion movements - Na+ and K+ diffuse in and out of cells through Leak channels (Open Channels) in the membrane - Na+ / K+ pumps, are present in the membrane of all cells, pumps Na+ out and K+ in - This sets up an unequal distribution of ions across the membrane (Pr = negative charged molecules i.e. phosphate, proteins, nucleic acids)

Na+/K+ ATPase: Maintains ionic composition of fluid around cells - Membrane transporter - Mechanism is primary active transport energy for conformational changes of the carrier comes directly from ATP hydrolysis - Pumps 3 Na+ out of cell and 2 K+ into cell for every ATP hydrolysed

Membrane potential: governed by membrane permeability

Equilibrium potentials Two forces (gradients) at work Chemical force for an ion versus the electrical force - Chemical force: moves K+ out as present at higher concentration inside - Electrical force: attracts K+ back into cell as negative charge accumulates inside - When the chemical and electrical forces exactly balance there will not be no net movement of K+. this is the equilibrium potential for K+

DEFINITIONS

Membrane potential: An electrical potential difference across the cell membrane

Equilibrium potential: The potential, for any ion, at which there is no net flux of that ion across the membrane because the chemical and electrical forces that tend to move the ion exactly balance. Described mathematically by the Nernst equation.

Resting membrane potential: Membrane potential of excitable cells (e.g. neurons) at rest. An equilibrium state in which there is no net flux of any ions across the cell membrane. Resting membrane potential is similar (but not identical) to the K+ equilibrium potential because at rest cells are much more permeable to K+ than to other ions.

Calculating the equilibrium potential the Nernst equation

Typical nerve cell ion concentration - For this cell the K+ equilibrium potential and hence the approximate value of resting membrane potential is: V=61 log [ion]o/[ion]i V=61 log 2/124 V= -109 mV Healthy cells at rest have negative membrane potentials Electrical signalling: depolarization and hyperpolarization • Electrical signalling depends on changes in membrane potential due to changes in membrane ion permeability and ion distribution. • Net flow of ions across a membrane depolarizes or hyperpolarizes the cell creating an electrical signal.

Lecture 8- PART 5 – SIGNALLING CONTINUED

Gated channels control ion permeability of neuronal membrane Channels: - Voltage gated: o Open and close in response to membrane potential changes. Selective for particular ions - Ligand-gated: o Open and close in response to binding of ligands. E.g. neurotransmitters to the extracellular side of the channel proteins - Mechanically- gated: o Open and close in response to physical forces. E.g. vibrations, stetch, etc.

Graded potentials: - Size/amplitude of depolarization or hyperpolarization is directly proportional to the stimulus strength - Usually occur at dendrites and cell body - Potentials lose strength with distance from the site of initiation due to current leach across non-insulated membrane and resistance from cytoplasm to current flow.

Graded potentials: subthreshold and suprathreshold

- two signals arriving close together in time may sum to produce a larger response. - If graded potentials are large enough (suprathreshold) they will initiate an action potential

Action potentials - All-or-none, occur if stimulus threshold or do not occur if stimulus subthreshold - Strength and duration of stimulus represented by frequency of action potentials - Usually occur at axon hillock - No reduction in strength with distance from site of initiation - No summation due to a refractory period

- Permit rapid signalling over long distances

Action potential: ion channels:

Action potential conduction: - In the axon, each section of membrane is in a different phase of the action potential.

Action potential conduction- mechanism

Saltatory conduction - Larger diameter axons conduct signals faster- less resistance to current flow - Saltatory conduction occurs along myelinated axons - Conduction is slowed in demyelinating disorders - Myelinated mammalian axon conducts at 120m/sec, unmyelinated axon at 2m/sec

WEEK 3: Lecture 9- SYNAPSES, SENSORY PHYSIOLOGY WEEK 3 PART 1- SYNAPSES Synapses: sites of cell-cell communication - A neuron may receive multiple inputs and make multiple synapses - At synapses, electrical signals in the presynaptic neuron are transmitted to the postsynaptic neuron or muscle cell

Two types of synapses: - Electrical synapses: electric current passes directly from prepostsynaptic cell through gap junctions - Chemical synapses: electrical signal is converted into chemical signal that is released from the presynaptic cell and acts on receptors on the postsynaptic cell.

Electron microscope images of synapses:

- CHEMICAL: synaptic vesicles are clustered in the presynaptic terminal opposite receptors on the postsynaptic membrane - ELECTRICAL: gap junctions appear as regions of close membrane apposition between pre and postsynaptic neurons

Gap junctions: - Intercellular channel is formed by the docking of two hemichannels composed of connexin or innexin proteins

Chemical transmission Involves many steps: 1) Neurotransmitter synthesis 2) Storage/release 3) Receptor binding 4) Inactivation

Neurotransmitter CLASSICAL - Acetylcholine (Ach) - Biogenic amines: o noradrenaline (norepinephrine) o Dopamine o Serotonin o Histamine - Amino acids: o Glutamate o Y-aminobutyric acid (GABA) o Glycine PEPTIDES - Substance p - Opioids (endorphins, enkephalins) UNCONVENTIONAL TRANSMITTERS

- Gases: nitric oxide (NO) - Purines: adenosine triphosphate (ATP) - Lipids: cannabinoids Neurotransmitters may cause excitation or inhibition EXCITATORY TRANSMITTER - excites the postsynaptic cell by depolarizing the membrane - response is referred to as an excitatory postsynaptic potential (EPSP) - if the EPSP is large enough (i.e. depolarization reaches threshold) it will trigger an action potential INHIBITORY TRANSMITTER  inhibits the postsynaptic cell by hyperpolarizing...