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Organ Systems I: Transmitters (Part 5)

I believe we're talking about NEUROtransmitters, here, but Brons is abstruse. Small molecule transmitters are fast acting in acute sensory and motor responses of nervous system. Both direct and indirect. Removed from synapse by diffusion, enzymes or reuptake. Drugs often work by affecting synthesis or removal of transmitters. The action of a neurotransmitter is determined by its receptors. One neurotransmitter may affect different types of receptors each with a different action.

OVERVIEW: THE NERVOUS SYSTEM

SOMATIC VS AUTONOMIC

Somatic nervous system has a single neuron from the CNS to the muscle, no ganglia, each axon branch innervates a muscle fiber. Uses ACh as transmitter in linking to nicotinic receptor on skeletal muscle. Alpha-motor neuron cell bodies are located within the ventral horn of the spinal cord and project axons to skeletal muscle. Efferent. Each axon branches to innervate several (up to thousands) of muscle fibers.

Autonomic nervous system (as vs Somatic) = ANS = parasympathetic and sympathetic nervous systems consist of two neurons in sequence, pre and post ganglionic neurons. Axons of preganglionic neurons synapse onto postganglionic neourons within Autonomic Ganglia. Postganglionic axon has varicosities that synapse on different cells, less specific target than somatic motor.


PARASYMPATHETIC VS SYMPATHETIC

((Sympathetic (red) and parasympathetic (blue) nervous system, from Gray's Anatomy 1918 (public domain)))

Parasympathetic (rest and digest) (cranial sacral) nervous system = PNS
--structure: from medulla has two ACh synapses, the first with a nicotinic receptor, the second with a muscarinic receptor. Preganglionic is a cholinergic neuron. Postganglionic neuron can be cholinergic or noradrenoergic.
--functions: actions that do not require immediate reaction.
--Preganglionic cells originate in cranium and sacrum. Cranial neurons start in brain stem, and project to head, thorax and abdomen. Sacral cells begin at S2, 3, 4 and go to pelvic viscera.
--Ganglia are closer to the area of innervation, sometimes within the target structure.

Sympathetic (fight or flight) nervous system (SNS)
--structure: uses one ACh transmitter in 1st synapse, and NE (norepinephrine) in neuro-muscular junction. Preganglionic neurons come from T1 to L2. Postganglionic cells begin in ganglia or adrenal medulla. Is both afferent and efferent: bidirectional.
--Ganglia form immediately lateral and inferior to the spinal nerve - the "chain ganglion". Also paravertebral (top of thorax) and prevertebral ganglia (a little farther out from chain and from mix thorax to lumbar). Paravertebral: superior, middle and inferior cervical ganglia. Prevertebral: celiac ganglion, superior and inferior mesenteric ganglia.
--function: Quick responses to stress. Up- and down-regulation of many homeostatic mechanisms. Prolonged activation can elicit the release of adrenaline from the adrenal medulla. Efferent messages can accelerate heart rate, increase BP, widen bronchial passages, decrease motility (movement) of the large intestine, constrict blood vessels, increase peristalsis in the esophagus, cause pupil dilation, piloerection (goose bumps) and perspiration (sweating). Afferent messages carry sensations such as heat, cold, or pain.


GETTING INTO THE NITTY GRITTY:
Note to self and others: I am still revising and reorganizing this section (below) because I have still not integrated it in any orderly way in my own mind. Please let me know if you have a good way of categorizing and comprehending neurotransmitters, receptors and synapses. Thanks.

Synapses are characterized by neurotransmitter released (ACh, NE, NO, etc) and receptor types on postsynaptic neuron (nicotinic, muscarinic, alpha or beta adrenoceptor). The receptor dictates the neurotransmitter's effect.

NEUROTRANSMITTERS
-- amino acids, peptides, and monoamines or other classification system
-- Approx 10 "small-molecule neurotransmitters" are known:
-- acetylcholine (ACh)
-- monoamines (epinephrine E, norepinephrine NE, dopamine DA, serotonin 5-HTP, and melatonin)
-- 3 or 4 aa's depending on definition: (glutamic acid, GABA, aspartic acid & glycine)
-- purines: (Adenosine, ATP, GTP and their derivatives)
-- fatty acids are also receiving attention as the potential endogenous cannabinoid.
-- Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been found, incl hormones (LH, insulin) that have local actions and long-range signalling properties.
-- Single ions such as synaptically-released zinc, are considered neurotransmitters by some.
-- major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA.

Neurotransmitter types in ANS:
cholinergic and catecholamine

CHOLINERGIC TRANSMITTERS
-- cholinergic means "related to the neurotransmitter acetylcholine". A substance is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct acting").
-- two types of receptors: nicotine and muscarine
-- The parasympathetic nervous system is entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholingeric.

ACh = aceytl choline
--synthesis by acetylCoA + choline => choline & acetate
--enzymes: choline acetyltransferase to synthesize, acetylcholine esterase (AChE) to break down
--receptors: nicotinic & muscarinic

CATECHOLAMINE TRANSMITTERS = NE, Epi, DA (dopamine)
-- derived from the amino acid tyrosine containing catechol and amine groups
-- some are biogenic amines
-- water soluble and are 50% bound to plasma proteins, so they circulate in the bloodstream
-- most abundant: epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine, all of which are produced by phenylalanine and tyrosine
-- tyrosine is created from phenylalanine by hydroxylation, also ingested, then sent to catecholamine secreting neurons
-- many kinds of reactions convert tyrosine to DA, then to NE and Epi
-- catecholamines are released by the adrenal glands in rxn to psychological stress or low blood sugar levels.
NOREPINEPHRINE & EPINEPHRINE
--derived from tyrosine, along with Dopamine, L-DOPA. Stages in derivation: tyrosine => L-dihydroxyphenylalanine (L-dopa) => dopamine (DA) => norepinephrine (NE) => epi
--epi from adrenal medulla
--removal via reuptake, diffusion, or destruction by monoamine oxidase (MAO) or catechol-O-methyl transferase

NEUROPEPTIDES
--any of the variety of peptides found in neural tissue; e.g. endorphins, enkephalins. About 100 different peptides are known in mammals.
--Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, cannabinoids, and even some gases, like nitric oxide (NO).
--cause relatively long term changes in ion channel permeability, # of receptors, gene transcription of proteins, etc.
--synthesis and packaging into vesicles in cell body, then axonal transport to axon terminal.
--slow destruction by enzymes extends effect
--co-release with other transmitters is the rule
--frequency of stimulation affects release of small mol and neuropep release: low fx causes release of small mols only, high fx causes both to be released.
--neuropeptide receptors are metabotropic in that they utilize both cAMP and IP3/DAG second messengers

agonist = a substance that binds to a specific receptor and triggers a response in the cell mimicking the action of an endogenous ligand (such as hormone or neurotransmitter) that binds to the same receptor. Full (activates), partial (bio response but not as much as intended ligand), antagonist (blocks receptor), inverse (reduces activation somehow), coagonist (needs help)...etc.

RECEPTOR TYPES
nicotinic in neuromuscular junctions and autonomic ganglia on postganglionic neurons
muscarinic on body tissues and CNS neurons
dopamine receptors for DA
adrenergic receptors for NE, Epi

Receptors can be activated or inactivated either by endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, thus stimulating or inhibiting a biological response.

ANDRENERGIC? RECEPTORS:
--alpha (IP3, DAG) regulate Ca++ and K+ channels
--beta (cAMP) regulate smooth muscles, metabolism, heart
--beta 1 and beta 2 receptors respond to NE and affected by drugs, (ex: propranolol blocks beta receptors to lower HR, ephedra acts like epi, cocaine and amphetamine inhibit reuptake prolonging action

SYNAPSE TYPES: COMBO OF TRANSMITTER AND RECEPTOR

nicotinic cholinergic
--NMJ synapse is this type
--ACh increases permeability of ionotropic-transmitter-gated Na/K channel, exitatory
--EPP exceeds threshold creating AP, and one axonal AP can initiate muscle AP via voltage gated Na+ channels

muscarinic cholinergic
--location: receptors in body tissues (mostly parasymp but some symp, ie sweat glands) and CNS
--excited by muscarine
--actions: decelerate heart via direct action on K+ channels, hyperpolarize membrane, also contract smooth muscle

axon varicosities = synapses along the axon
EPP = end plate potential

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