intro to CNS Flashcards
biological membranes and ions
protein families that allow ionic passage
membranes are impermeable to ions, lipid bilayer is very hydrophobic
ATPase driven pumps, transporters, ion channels
ion channels: integral membrane proteins, multiple membrane-spanning domains, form a hydrophobic channel in the center, selective for ions and regulated by changes in the cell environment, multiple gene products/multiple subunits, glycosylated on extracellular side, consensus sequences for kinases, exhibit specificity for the ions that permeate the channel, ionic movement is driven by its electrochemical gradient
functional classification of ion channels based upon the gating mechanism
passive: non-gated, always open
active: gated (the closed and open states of the channel are regulated)
types of gating: membrane potential difference –voltage gated, small extracellular molecules – neurotransmitters, other membrane proteins, intracellular molecules (ions ATP)
Leak channel: is open at resting membrane potential (can be active or passive, all passive channels are leak channels
resting membrane potential
a potential difference exists across the membrane of excitable cells. in neurons, Em/ Vm= -60mV
the negative resting membrane potential arises from: most intracellular proteins are anions, leak channels are present in the plasma membrane that K+ and Cl- can move, conductance (g) of the membrane to K is approximately 100 times greater than Na so there is an unequal distribution of Cl, K, and Na across the membrane. K is high on the inside, Na and Cl are high on the outside.
creates an electrochemical potential:
Nernst electrochemical equilibriums: (K= -90 mV, Na=+50, Cl= -70
some of the leak is opposed by the Na/K ATPase pump that moves Na out of the cell and K into the cell
action potentials
occur because voltage operated Na channels open in the membrane in response to localized depolarization
V=IR, increased Na current results in change in V
Voltage gated potassium channels also open, but gradually and inactivate slowly
APs are all or none, amplitude of about 100 mV, 1-10 msec in duration, propagated through cycles of depolarization and repolarized
synaptic potentials
small, graded potentials that can lead to initial depolarization that causes an action potential, local, can summate in time and space, only a few mV in size and a few msec in duration, 2 types of synaptic EPSPs= membrane potentials become more positive if it increases enough, threshold will be reached.
IPSPs= membrane potential moves to more negative values, impact is on a summating EPSP which will not reach threshold.
2 mechanisms by which an EPSP can occur
- Increased conductance: open a ligand gated ion channel for sodium or calcium, nicotinic cholinergic receptors, glutamate receptor
- Decreased conductance: close a leak channel for potassium (via phosphorylation, regulated by GPCRs)
mechanism for the production of IPSPs
increased conductance of the membrane to either potassium of chloride: ligand gated chloride channel (GABA receptor)
GPCR activation–> opening of K channels, direct interactions between the channel protein and G protein –> closing K channels
biogenic amines neurotransmitters
catecholamines (Dopamine, Norepinephrine, Epinephrine)
Indolamines (serotonin)
neuropeptides
beta-endorphin, orexin, neurotensin
Over 100 neuropeptides known
amino acids
glutamate, gamma-aminobutyric acid (GABA)
ionotropic neurotransmitter receptors
binding of the NT ligand directly opens the channel, which is an integral part of the receptor complex
channel opens quickly
AMPA glutamate receptors (Na and K), GABA receptors (Cl-)
metabotropic NT receptors
binding to the receptors engages a G protein, which results in the production of 2nd messengers that mediate intracellular signaling cascades
Effects can last tens of seconds to minutes
Membrane-delimited pathways of metabotropic receptors: modulation of voltage-gated channels
diffusible second messengers of metabotropic receptors: (cAMP by Gs PCR)
steps in synaptic transmission (druggable targets)
synthesis of NT, packaging into pre synaptic element in prep for release, release of NT into cleft, binding of NT to receptor, termination of NT action
general principle of CNS pharmacology
A CNS active drug must penetrate the BBB (composed of tight endothelial tight junctions supported by astrocyte foot processes)
nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission, many CNS disrders involve multiple brain regions and pathways
a CNS- active drug may act at multiple sites with disparate and even opposing effects
