membrane function: permeability

meyer overton rule

• used by pharmaceutical companies

• preducts penetration of anaesthetics as inc lipid solubility inc penetration

lipid permeability and pH and cocaine

• high pH high lipid permeability

• cocaine more likely to disassociate under high pH, becomes more lipid soluble

class of membrane transport protein i - ion channels

• passive

• high rate of transport

• eg GABAA receptor, pentameric, restricts flow for chloride ions

class of membrane transport protein ii - ion pumps

• transport one or more substrate (at least one against gradient)

• enzymatic activity ATPase, hydrolysis of ATP to release energy for ion transport (primary active transport)

• eg Na+/K+ ATPase

• very slow compared to ion channel

3 types of intracellular ion pumps

• P type - flippases

• F type - found in mitochondria

• V type - H+ pump in cell organelles

ATP binding cassette proteins

• p glycoprotein bestows drug resistance

• CFTR anion channel mutated in cystic fibrosis

• sulphonylurea receptor - ATP sensitive K+ channel

class of membrane transport iii - solute carriers SLC

• transport one or more substance - at least one down gradient

• extremely diverse - 66 subfamilies and 5 non canonical sub families

• even slower than ion channels and ion pumps

• 2nd most diverse group of proteins after GPCR

• important drug targets

• exchangers and cotransporters

examples of solute carriers SLC

1. facilitated diffusion with GLUT transporters

2. cotransporters (symports) two or more substrates in the same direction, Na+ glucose cotransport, secondary active transport

3. exchangers (antiports) - two or more substrates transported in opposite directions - Na+, H+ exchange (pH), bicarbonate and chloride

EGABA

• It is the reversal potential for the GABA-A receptor.

• It is determined by the concentration gradient of Chloride.

• It dictates whether GABA will hyperpolarize (inhibit) or depolarize (excite) a neuron.

• if Vm is more pos than EGABA then opening of GABA-A - hyperpolarisation

• if Vm is more negative than EGABA then closing of GABA-A - depolarisation

• It is maintained by SLC transporters

SLC drug targets 

• established

  • amphetamines → NET and dopamine

  • SSRIs → inhibitors or Na+ serotonin cotransporter

• new

  • SGLT2 inhibitors for diabetes

• potential

  • immunomodulation, anti cancer…

discoverty of aquaporins

• peter agre

• identified 28 KDa protein

• oocytes exposed ot hypotonic solution

• oocytes expressing aquaporins burst

  • indicates h2o channel

where are there many aquaporins

• kidney collecting duct 

• insertion of aquaporin 2 is inc by vasopressin , inc permeability to water 

brain inflammation and aquaporin 4

• family of 9 proteins

• AQP4 knockout mouse gene

  • inc survival, lower detrimental effect from middle cerebral artery occlusion

  • dec brain inflammation in experimental model of stroke